Benzoxazepine-2-one compounds and their use

ABSTRACT

Disclosed is a squalene synthetase inhibitor which comprises the compound represented by the formula (I) ##STR1## wherein R 1  stands for H or an optionally substituted hydrocarbon group; R 2  and R 3  independently stand for H, an optionally substituted alkyl group, an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic group; Z stands for a carbon chain containing a double bond or --Z&#39;--C(OH)-- (Z&#39; stands for a bond or a straight-chain or branched alkylene chain); the symbol ......... stands for a double bond or a single bond; Y stands for an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, an optionally substituted amino group or an optionally substituted heterocyclic radical having a protonizable hydrogen; X stands for O or S; G stands for O or S; and the ring A is optionally substituted, or a pharmaceutically acceptable salt thereof, and which is useful for the prophylaxis or therapy of hypercholesteremia or coronary sclerosis of mammals.

This application is a continuation of application Ser. No. 08/312,194,filed Sep. 26, 1994 abandoned.

FIELD OF THE INVENTION

This invention relates to a condensed 7-membered cyclic compound or asalt thereof, and, to a squalene synthetase inhibitor comprising same asthe effective component.

BACKGROUND OF THE INVENTION

Hypercholesteremia, high blood pressure and smoking are known as threemajor dangerous factors of causing ischemic heart diseases. Adequatecontrol of cholesterol concentration in blood is remarkably importantfor the prophylaxis or therapy of, besides these ischemic heartdiseases, as well as of coronary sclerosis.

As pharmaceutical compositions for lowering cholesterol in blood,attention has been drawn to those for controlling the biosynthesis ofcholesterol, besides those of inhibiting its absorption by binding bileacid including, among others, cholestyramine, colestipol (disclosed in,for example, U.S. Pat. No. 4,027,009), and those of suppressing theintestinal absorption of cholesterol by inhibiting acyl coenzyme Acholesterol acyl transferase (ACAT) including melinamide (disclosed inFrench Patent No.1476569). As pharmaceutical preparations forcontrolling the biosynthesis of cholesterol, lovastatin (disclosed inU.S. Pat. No. 4,231,938), simvastatin (disclosed in U.S. Pat. No.4,444,784), pravastatin (U.S. Pat. No. 4,346,227), etc., which arecapable of inhibiting especially 3-hydroxy-3-methyl glutaryl coenzyme(HMG-CoA) reductase, are provided for medicinal use. However, whenHMG-CoA reductase is inhibited, not only the biosynthesis of cholesterolbut the biosynthesis of some other components such ubiquinone, dolicholand heme A, which are necessary for the living body, is also inhibited,so that occurrences of undesirable side effects to be caused thereby arefeared.

Squalene synthetase is an enzyme taking part in the essential step ofnew cholesterol biosynthetic route. And, this enzyme is an enzymeforming squalene catalyzing the reductive dimerization of two moleculesof farnesyl pyrophosphoric acid.

On the other hand, the compounds expected as inhibitors of cholesterolbiosynthesis by inhibiting squalene synthetase are disclosed in Journalof Medicinal Chemistry, Vol. 51, No. 10, pp. 1869-1871, 1988, Japanesepublished unexamined patent application No. H1-213288/1989(JPAH1(1989)-213288), JPA H2(1990)-101088, JPA H2(1990)-235820, JPAH2(1990)-235821, JPA H3(1991)-20226, JPA H3(1991)-68591, JPAH3(1991)-148288 and U.S. Pat. No. 5,019,390, U.S. Pat. No. 5,135,935,WO9215579, WO9309155 and WO9313096.

And, various compounds showing antifungal action by inhibiting thesynthesis of squalene have been known (JPA H4(1992)-279589, EP-475706,EP-494622, EP-503520, among others).

Among 4,1-benzoxazepine derivatives, in 4,1-benzoxazepin-2-onederivatives in which 2-position is substituted with ketone group, thosein which one of the hydrogen atoms at 3-position is replaced with adifferent substituent, are disclosed in JPA S57(1982)-345765 and Chem.Pharm. Bull., 34, 140 (1986).

OBJECT OF THE INVENTION

Ubiquinone, dolichol and heme A have been known as being synthesizedfrom farnesyl pyrophosphate along the cholesterol biosynthesis pathway.Therefore, for avoiding occurrence of side effects due to loss of thesesubstances, it is desirable to inhibit enzyme systems subsequent tofarnesyl pyrophosphate, especially squalene synthetase, in thecholesterol biosynthetic pathway.

SUMMARY OF THE INVENTION

The present inventors have, taking the above-mentioned circumstancesinto consideration, made diligent research work, and found that4,1-benzoxazepin-2-one derivatives have an excellent action ofinhibiting squalene synthetase, and further have an antifungal action aswell, thus the present invention being accomplished.

More specifically, the present invention is to provide

(1) a condensed 7-membered cyclic compound represented by the formula(I) ##STR2## wherein R₁ stands for H or an optionally substitutedhydrocarbon group; R₂ and R₃ independently stand for H, an optionallysubstituted alkyl group, an optionally substituted phenyl group or anoptionally substituted aromatic heterocyclic group; Z stands for acarbon chain containing a double bond or --Z'--C(OH)--(Z' stands for abond or a straight-chain or branched alkylene chain); the symbol......... stands for a double bond or a single bond; Y stands for anoptionally esterified carboxyl group, an optionally substitutedcarbamoyl group, an optionally substituted hydroxyl group, an optionallysubstituted amino group or an optionally substituted heterocyclicradical having protonizable hydrogen; and the ring A is optionallysubstituted or a salt thereof, and

(2) a squalene synthetase inhibitor comprising the condensed 7-memberedcyclic compound represented by the formula (I) or a salt thereof.

Further, the present invention is to provide a method of producing anovel compound represented by the formula (I) or a salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

In the above formulae (I), as the hydrocarbon group of the "optionallysubstituted hydrocarbon groups" shown by R₁, mention is made ofaliphatic chain-like hydrocarbon groups, alicyclic hydrocarbon groupsand aryl groups, etc., among them, aliphatic chain-like hydrocarbongroups being preferable.

As the aliphatic chain-like hydrocarbon groups of said hydrocarbongroups, mention is made of, for example, straight-chain or branchedaliphatic hydrocarbon groups, such as alkyl group, alkenyl group,alkynyl group, etc., among them, alkyl groups being preferable. As thealkyl group, mention is made of, for example, C₁₋₇ alkyl such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, etc., and, among them, C₃₋₅alkyl groups such as n-propyl, isopropyl, isobutyl, neopentyl, etc. arepreferable, further, isobutyl, neopentyl being preferable. As the saidalkenyl group, mention is made of, for example, C₂₋₆ alkenyl such asvinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl,2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc., and, amongthem, vinyl, allyl, isopropenyl, 2-methylallyl, 2-methyl-1-propenyl,2-methyl-2-propenyl, 3-methyl-2-butenyl, etc. are especially preferable.As the said alkynyl group, mention is made of, for example, C₂₋₆ alkynylsuch as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc., and, among them,ethynyl, 1-propynyl, 2-propynyl, etc. are especially preferable.

Examples of the alicyclic hydrocarbon groups of said hydrocarbon groupinclude saturated or unsaturated alicyclic hydrocarbon groups such ascycloalkyl group, cycloalkenyl group, cycloalkadienyl group, etc. Assaid cycloalkyl group, C₃₋₉ cycloalkyl groups are preferable, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, etc. are mentioned, and, among them, C₃₋₆cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc. are preferable. As said cycloalkenyl group, mention ismade of, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl,1-cyclopenten-1-yl, etc. As said cycloalkadienyl group, mention is madeof, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl,2,5-cyclohexadien-1-yl, etc.

As the aryl group of said hydrocarbon group, mention is made ofmono-cyclic or condensed polycyclic aromatic hydrocarbon groups, forexample, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, etc.,and, among them, phenyl, 1-naphthyl, 2-naphthyl, etc. are especiallypreferable.

As substituents of the "optionally substituted hydrocarbon groups" shownby R₁, mention is made of optionally substituted aryl groups, optionallysubstituted cycloalkyl groups or cycloalkenyl groups, optionallysubstituted heterocyclic groups, optionally substituted amino groups,optionally substituted hydroxyl groups, optionally substituted thiolgroups, halogen (e.g. fluorine, chlorine, bromine, iodine), etc., and,the hydrocarbon group shown by R₁ is optionally substituted with 1 to 5(preferably 1 to 3) of these substituents at any possible position. Asaryl groups of said optionally substituted aryl groups, mention is madeof phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, etc., and,among them, phenyl, 1-naphthyl and 2-naphthyl are preferable. Assubstituents of said optionally substituted aryl, mention is made ofC₁₋₃ alkoxy groups (e.g. methoxy, ethoxy, propoxy, etc.), halogen atoms(e.g. fluorine, chlorine, bromine, iodine), C₁₋₃ alkyl groups (e.g.methyl, ethyl, propyl, etc.), and the aryl is optionally substitutedwith one or two of optional ones of them. As cycloalkyl groups of saidoptionally substituted cycloalkyl groups, mention is made of C₃₋₇cycloalkyl groups including cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, etc. The kinds and number of the substituentsof said optionally substituted cycloalkyl groups are substantially thesame as those in the case of the above-mentioned aryl groups. Ascycloalkenyl groups of said optionally substituted cycloalkenyl groups,mention is made of, among others, C₃₋₆ cycloalkenyl groups such ascyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. The kindsand number of the substituents of said optionally substitutedcycloalkenyl groups are substantially the same as those in the case ofthe above-mentioned optionally substituted aryl groups. As heterocyclicgroups of said optionally substituted heterocyclic groups, mention ismade of, aromatic heterocyclic groups having, as the atoms (cyclicatoms) constituting the cyclic system, at least one hetero-atom selectedfrom oxygen, sulfur and nitrogen, and saturated or unsaturatednon-aromatic heterocyclic groups (aliphatic heterocyclic groups),preferably aromatic heterocyclic groups. As said aromatic heterocyclicgroups, mention is made of aromatic mono-cyclic heterocyclic groups(e.g. furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,triazinyl, etc.) and aromatic condensed heterocyclic groups.(e.g.benzofuranyl, isobenzofuranyl, benzo b!thienyl, indolyl, isoindolyl,1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl,benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl,β-carbolinyl, γ-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl,phenanthrolinyl, indolizinyl, pyrrolo 1,2-b!pyridazinyl, pyrazolo1,5-a!pyridyl, imidazo 1,2-a!pyridyl, imidazo 1,5-a!pyridyl, imidazo1,2-b!pyridazinyl, imidazo 1,2-a!pyrimidinyl, 1,2,4-triazolo4,3-a!pyridyl, 1,2,4-triazolo 4,3-b!pyridazinyl, etc.), and, among them,furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl,etc. are preferable. Examples of said non-aromatic heterocyclic groupsinclude oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, piperazinyl, etc. As substituents of said optionallysubstituted heterocyclic groups, mention is made of C₁₋₃ alkyl groups(e.g. methyl, ethyl, propyl, etc.). Examples of substituents of saidoptionally substituted amino groups, optionally substituted hydroxylgroups and optionally substituted thiol groups include lower (C₁₋₃)alkyl (e.g. methyl, ethyl, propyl, etc.). And, when the hydrocarbongroups in the optionally substituted hydrocarbon groups shown by R₁ arealicyclic hydrocarbon groups or aryl group, they may have, assubstituents, C₁₋₃ alkyl groups (e.g. methyl, ethyl, propyl, etc.)

As the alkyl groups of "optionally substituted alkyl groups" shown by R₂and R₃, mention is made of C₁₋₆ lower alkyl groups (e.g. methyl, ethyl,n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, isohexyl, etc.), and, among them, C₁₋₄alkyl groups including methyl, ethyl, propyl, isopropyl, butyl andt-butyl are preferable. As the substituents of said optionallysubstituted lower alkyl groups, mention is made of halogen (e.g.fluorine, chlorine, bromine, iodine), C₁₋₄ lower alkoxy groups (e.g.methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, etc.).

As substituents of "optionally substituted phenyl groups" shown by R₂and R₃, mention is made of halogen atoms (e.g. fluorine, chlorine,bromine, iodine), an optionally substituted lower alkyl, an optionallysubstituted lower alkoxy, an optionally substituted hydroxyl group,nitro group, cyano group, etc., and the phenyl group may be preferablysubstituted with 1 to 3 substituents (preferably 1 to 2) of thesesubstituents at any possible positions. As the lower alkyl, mention ismade of, for example, C₁₋₄ alkyl groups including methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc., andespecially methyl and ethyl are preferable. As the lower alkoxy, mentionis made of C₁₋₄ alkoxy groups including methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., andespecially methoxy and ethoxy are preferable. As substituents of saidoptionally substituted lower alkyl groups or optionally substitutedlower alkoxy groups, mention is made of halogen atoms (e.g. fluorine,chlorine, bromine, iodine, etc.), and one to five of these mayoptionally substituted at an optional possible position. As substituentsat said optionally substituted hydroxyl group, mention is made of, forexample, C₁₋₄ alkyl groups (e.g. methyl, ethyl, propyl, isopropyl,butyl, t-butyl, etc.), C₃₋₆ cycloalkyl groups (cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, etc.), aryl groups (e.g. phenyl, 1-naphthyl,2-naphthyl, etc,), aralkyl groups (e.g. benzyl, phenethyl, etc.). And,these substituents may form a ring together with the adjacentsubstituents to each other, for example, the following is mentioned:##STR3## Said ring may be substituted with a lower (C₁₋₃) alkyl (e.g.methyl, ethyl, propyl, isopropyl, etc.) and the like.

As aromatic heterocyclic groups of the "optionally substituted aromaticheterocyclic groups" shown by R₂ and R₃, mention is made of aromaticheterocyclic groups described in detail referring to R₁, and, amongthem, furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl,pyrimidyl, imidazolyl, etc. are preferable. As substituents of saidaromatic heterocyclic groups, mention is made of C₁₋₃ alkyl groups (e.g.methyl, ethyl, propyl, etc.).

Among the above-exemplified groups represented by R₂ and R₃, optionallysubstituted phenyl groups, preferably substituted phenyl groups arepreferable, with greater preference given to a phenyl group substitutedwith halogen, lower alkoxy, etc.

As the "carbon chain containing double bond" shown by Z, mention is madeof, preferably, those in which the carbon number constituting thestraight-chain portion ranges from 1 to 7, more preferably 1 to 4, andthey may optionally have side chains. While the double bond at saidcarbon chain is contained in the straight-chain portion and/or branchedchain portion, it is contained preferably in the straight-chain portion.Number of the double bond contained in said carbon chain is notrestricted as far as possible, it ranges preferably from 1 to 2.

Examples of carbon chains containing said double bond include methine,vinylene, propenylene, butenylene, butadienylene, methylpropenylene,ethylpropenylene, propylpropenylene, methylbutenylene, ethylbutenylene,propylbutenylene, methylbutadienylene, ethylbutadienylene,propylbutadienylene, pentenylene, hexenylene, heptenylene,pentadienylene, hexadienylene and heptadienylene, preferably methine,vinylene, propenylene, butenylene and butadienylene.

Examples of the "straight-chain or branched alkylene chain" shown by Z'include straight-chain or branched C₁₋₆ alkylene chain, morespecifically, divalent ones such as methylene, ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene, heptamethylene,propylene, ethylmethylene, ethylethylene, propylethylene, butylethylene,methyltetramethylene and methyltrimethylene, and, preferably, C₁₋₃ onessuch as methylene, ethylene, trimethylene and propylene.

As the "optionally esterified carboxyl group" shown by Y, mention ismade of lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl,etc.), aryloxycarbonyl (e.g. phenoxycarbonyl, 1-naphthoxycarbonyl,benzyloxycarbonyl, etc.) etc., and, among them, carboxyl group,methoxycarbonyl and ethoxycarbonyl are preferable.

Examples of substituents of the "optionally substituted carbamoyl group"shown by Y include optionally substituted lower (C₁₋₆) alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.),optionally substituted C₃₋₆ cycloalkyl groups (e.g. cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, etc.), optionally substituted arylgroup (e.g. phenyl, 1-naphthyl, 2-naphthyl, etc.), optionallysubstituted aralkyl groups (e.g. benzyl, phenethyl, etc.), and, one ortwo of these substituents may independently substituted. As substituentsat said optionally substituted lower (C₁₋₆) alkyl and optionallysubstituted C₃₋₆ cycloalkyl group, mention is made of, carboxyl groupoptionally esterified with a lower (C₁₋₅) alkyl (e.g. methyl, ethyl,propyl, isopropyl, butyl, t-butyl, pentyl, isopentyl, neopentyl, etc.),aromatic heterocyclic groups (e.g. furyl, thienyl, indolyl, isoindolyl,pyrazinyl, pyridyl, pyrimidyl, imidazolyl, etc.), amino group, hydroxylgroup, phenyl group, etc., and, one to three of these substituents mayindependently substituted. As substituents of said optionallysubstituted aryl groups and optionally substituted aralkyl groups,mention is made of, halogen atoms (e.g. fluorine, chlorine, bromine,iodine), carboxyl groups optionally esterified with a lower (C₁₋₄) alkyl(e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.). And, twosubstituents on a nitrogen atom may form a cyclic amino group takentogether with the nitrogen atom. Examples of such cyclic amino groupinclude 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino,1-piperazinyl, etc.

Examples of substituents of the "optionally substituted hydroxyl groups"shown by Y include lower (C₁₋₄) alkyl (e.g. methyl, ethyl, propyl,isopropyl, butyl, t-butyl, etc.), C₃₋₆ cycloalkyl groups (e.g.cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), optionallysubstituted aryl groups (e.g. phenyl, 1-naphthyl, 2-naphthyl, etc.),optionally substituted aralkyl groups (e.g. benzyl, phenethyl, etc.),etc. As substituents of said optionally substituted aryl group andoptionally substituted aralkyl group, mention is made of halogen atoms(e.g. fluorine, chlorine, bromine, iodine), carboxyl groups optionallyesterified with lower (C₁₋₄) alkyl (e.g. methyl, ethyl, propyl,isopropyl, butyl, t-butyl, etc.), etc.

Examples of substituents of the "optionally substituted amino groups"shown by Y include lower (C₁₋₄) alkyl (e.g. methyl, ethyl, propyl,isopropyl, butyl, t-butyl, etc.), C₃₋₆ cycloalkyl groups (e.g.cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), optionallysubstituted aryl groups (e.g. phenyl, 1-naphthyl, 2-naphthyl, etc.),optionally substituted aralkyl groups (e.g. benzyl, phenethyl, etc.),etc. As substituents of said optionally substituted aryl group andoptionally substituted aralkyl group, mention is made of halogen atoms(e.g. fluorine, chlorine, bromine, iodine), carboxyl groups optionallyesterified with lower (C₁₋₄) alkyl (e.g. methyl, ethyl, propyl,isopropyl, butyl, t-butyl, etc.), etc. And, two substituents on anitrogen atom may form a cyclic amino group taken together with thenitrogen atom. Examples of the cyclic amino group include 1-azetidinyl,1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl, etc.

As heterocyclic radicals of the "optionally substituted heterocyclicradical having a protonizable hydrogen" shown by Y, mention is made of5-7 membered (preferably 5 membered) monocyclic heterocyclic radicalcontaining at least one hetero atom selected from the group consistingof N, S and O, more preferably N-containing heterocyclic radical.Especially, tetrazol-5-yl and groups represented by the formula ##STR4##wherein i stands for --O-- or --S--; j stands for >C═O, >C═S or >SO₂,(especially 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl,2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl,2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) are preferable.

Said heterocyclic radical may be protected with an optionallysubstituted lower alkyl (preferably C₁₋₄ alkyl), acyl, etc. As saidoptionally substituted lower alkyls, mention is made of methyl,triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl,p-nitrobenzyl, etc. Examples of said acyl include lower (C₂₋₅) alkanoyl,benzoyl, etc.

Among the above-exemplified groups shown by Y, an optionally esterifiedcarboxyl group and an optionally substituted carbamoyl group arepreferable.

As substituents of the ring A, mention is made of hydroxyl group,halogen (e.g. fluorine, chlorine, bromine, iodine), nitro, cyano, C₁₋₄lower alkyl groups (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, etc.) and C₁₋₄ lower alkoxy group (e.g.methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,tert-butoxy, etc.), and, methyl, ethyl, methoxy, ethoxy and chlorine arepreferable, especially, methoxy and chlorine are preferable. One or twoof these substituents may independently substituted.

Practical examples of the compounds of this invention are disclosed asfollows:

(3RS,5RS,αSR)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester,

(3RS,5SR,αSR)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester,

7-Chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester,

7-Chloro-5-(2-chlorophenyl)-1-propyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester,

(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid,

(3RS,5RS,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid,

(3RS,5RS,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid,

(3RS,5RS,αRS)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid,

(3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid,

(3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester,

(3RS,5RS,αRS)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester,

(E)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,Δ)-aceticacid ethyl ester,

(E)-7-Chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(2-chlorophenyl)-2-oxo-1-isopropyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid ethyl ester,

(E)-7-Chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid ethyl ester,

(E)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid,

(3RS,5SR,αRS)-7-Chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid ethyl ester,

(3RS,5SR,αSR)-7-Chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid ethyl ester,

(3RS,5SR,αRS)-7-Chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid,

(3RS,5SR,αSR)-7-Chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid,

(3RS,5SR,αRS)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid ethyl ester,

(3RS,5SR,αSR)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid ethyl ester,

(3RS,5SR,αRS)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid,

(3RS,5SR,αSR)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid,

(3RS,5SR,αRS)-7-Chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid ethyl ester,

(3RS,5SR,αSR)-7-Chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid ethyl ester,

(3RS,5SR,αRS)-7-Chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid,

(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid,

N-(3RS,5SR,αSR)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolyl!aminoaceticacid ethyl ester,

N-(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolyl!aminoaceticacid,

N-(E)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-acetyl!aminoaceticacid ethyl ester,

N-(E)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-acetyl!aminoaceticacid,

N-(E)-7-Chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-acetyl!aminoaceticacid ethyl ester,

N-(E)-7-Chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-acetyl!aminoaceticacid,

N-(E)-7-Chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-acetyl!aminoaceticacid ethyl ester,

N-(E)-7-Chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-acetyl!aminoaceticacid,

(E)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(2,4-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(2,4-dimethoxyphenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(3-hydroxy-2-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(4-hydroxy-2-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(3-hydroxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(4-hydroxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(3-hydroxy-2-methoxyphenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(4-hydroxy-2-methoxyphenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(3-ethoxy-2-methoxyphenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(4-ethoxy-2-methoxyphenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(3-ethoxy-2-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(4-ethoxy-2-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(3-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(2-chloro-4-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(2-chloro-4-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(2-methoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid,

(E)-7-Chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid, and

(E)-7-Chloro-5-(2-methoxyphenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-aceticacid.

As salts of the compound (I), mention is made of pharmaceuticallyacceptable ones, for example, inorganic salts such as hydrochloride,hydrobromide, sulfate, nitrate, phosphate, etc., organic salts such asacetate, tartrate, citrate, fumarate, maleate, toluenesulfonate,methanesulfonate, etc., metal salts such as sodium salt, potassium salt,calcium salt, aluminum salt, and salts with a base such as triethylaminesalt, guanidine salt, ammonium salt, hydrazine salt, quinine salt,cinchonine salt, etc.

The method of producing the compound of this invention is describedbelow.

Among compounds represented by the formula (I), the compound representedby the formula (Ia) ##STR5## wherein R₄ shows the alkyl portion of theesterified carboxyl group defined by Y, and other symbols are of thesame meaning as defined in the foregoing can be produced by thefollowing process: ##STR6## wherein symbols are of the same meaning asdefined above.

The method of producing the compound represented by the formula (IV) byallowing the compound represented by the formula (II) to react with thecompound represented by the formula (III) comprises acylation of aminogroup, which can be conducted easily by a per se known method. Morespecifically, the reaction can be conducted in a solvent, for example,ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., halogentype solvents such as dichloromethane, dichloroethane, chloroform,carbon tetrachloride, etc., hydrocarbons such as benzene, toluene,hexane, heptane, etc., dimethylformamide, dimethyl sulfoxide, and, whennecessary, in the presence of water and a base (e.g. an organic basesuch as 4-dimethylaminopyridine, triethylamine, triethylenediamine,tetramethylethylenediamine, etc., an inorganic base such as sodiumhydrogencarbonate, potassium hydrogencarbonate, sodium carbonate,potassium carbonate, sodium hydroxide, potassium hydroxide, etc. sodiumhydride, potassium hydride), etc. Relative to one mole of the compoundrepresented by the formula (II), the acid chloride represented by theformula (III) is employed usually in an amount of 1 to 10 moles,preferably about 1 to 3 moles. The reaction time ranges usually fromabout 1 to 48 hours, preferably about 5 to 10 hours. The reactiontemperatures range from -50° to 100° C., preferably from 0° to 50° C.

The method of producing a compound represented by the formula (Ia) froma compound represented by the formula (IV) can be conducted in asolvent, for example, an ether type solvent such as diethyl ether,tetrahydrofuran, dioxane, etc.; a halogen type solvent such asdichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.;a hydrocarbon type solvent such as benzene, toluene, hexane, heptane,etc.; an alcohol type solvent such as methanol, ethanol, propanol, etc.;dimethylformamide, dimethyl sulfoxide, etc., and, upon necessity, in thepresence of a base (e.g. an organic base such as4-dimethylaminopyridine, triethylamine, triethylenediamine,tetramethylethylenediamine, etc. or, e.g. sodium hydrogencarbonate,potassium hydrogencarbonate, sodium carbonate, potassium carbonate). Thereaction time ranges from one hour to 24 hours, preferably from 5 hoursto 20 hours. The reaction temperatures roughly range from 0° to 100° C.,preferably from 20° to 50° C.

The compound represented by the formula (II) employable as a startingmaterial can be synthesized by the method described in D. A. Walsh.Synthesis. 677 (1980) or methods referred to in said literaturereference, or methods analogous thereto.

Among the compounds represented by the formula (I), production of acompound represented by the formula (Ib) ##STR7## wherein symbols are ofthe same meaning as defined above! can be carried out by subjecting thehydroxyl group of the compound represented by the formula (Ia) tomethanesulfonylation or toluenesulfonylation. The reaction itself is aconventional one, and the object compound can be produced bysubstantially the same method as that for producing the compoundrepresented by the formula (IV) from the compound represented by theformula (II) and the compound represented by the formula (III).Subsequently, thus methanesulfonylated or toluenesulfonylated compoundscan be subjected to reaction in a solvent, for example, an ether typesolvent such as diethyl ether, tetrahydrofuran, dioxane, etc.; a halogentype solvent such as dichloromethane, dichloroethane, chloroform, carbontetrachloride, etc.; and a hydrocarbon type solvent such as benzene,toluene, hexane, heptane, etc.; dimethylformamide, dimethyl sulfoxide,etc., and, upon necessity, in the presence of a base (for example, anorganic base such as 4-dimethylaminopyridine, triethylamine,triethylenediamine, tetramethylethylenediamine, etc.; an inorganic basesuch as sodium hydrogencarbonate, potassium hydrogencarbonate, sodiumcarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide,etc.; sodium hydride, potassium hydride, sodium methoxide, sodiumethoxide, sodium hydride, sodium acetate, potassium acetate, sodiumpropionate, cesium propionate, potassium tert-butoxide) etc. The amountof the base ranges from 1 to 10 molar equivalents, preferably about from1 to 2 molar equivalents relative to one mole of the methanesulfonylatedor toluenesulfonylated compound. The reaction time usually ranges fromone to 24 hours, preferably from 5 to 10 hours, and the reactiontemperatures range from 0° to 200° C., preferably from 50° to 100° C.Among the compounds of the formula (I), a compound represented by theformula (Ic) ##STR8## wherein each symbol has the same meaning asdefined above can be produced by converting a compound represented bythe formula (V) ##STR9## wherein each symbol is of the same meaning asdefined above, to cyanohydrin, then by subjecting the cyano group tohydrolysis. The production of the cyanohydrin can be conducted byallowing the compound represented by the formula (V) to react in acetonecyanohydrin, and, upon necessity, in the presence of a base (forexample, 4-dimethylaminopyridine, triethylamine, triethylenediamine,etc.). The reaction time ranges from 10 minutes to 5 hours, preferablyfrom 30 minutes to 2 hours, and the reaction temperatures range from 0°to 100° C., preferably about 20° to 50° C. The amount of the base to beemployed ranges from 0.1 to 3 molar equivalents, preferably from about0.2 to 0.5 molar equivalents, relative to one mole of the compoundrepresented by the formula (V). Hydrolysis of thus-obtained cyanohydrincan be conducted by a per se known method, in the presence of, as asolvent, an alcohol type solvent such as methanol, ethanol or propanol,and an acid((e.g. hydrogen chloride, sulfuric acid). The reactiontemperature ranges from 30° to 150° C., preferably from about 50° to100° C. The reaction time ranges from 10 minutes to 5 hours, preferablyfrom about 30 minutes to one hour.

Among the compounds of the formula (I), a compound of the formula (Id)##STR10## wherein Z" and Z'" respectively stand for a carbon chainoptionally containing a bond or a double bond, and other symbols are ofthe same meaning as defined above can be produced by allowing a compoundrepresented by the formula (V') ##STR11## wherein each symbol is of thesame meaning as defined above! to react with a compound represented bythe formula (VI)

    Ph.sub.3 P═CH--Z"'--COOR.sub.4                         (VI)

wherein symbols are of the same meaning as defined above. The reactionis conducted in a solvent, for example, an ether type solvent such asdiethyl ether, tetrahydrofuran, dioxane, etc., a halogen type solventsuch as dichloromethane, dichloroethane, chloroform, carbontetrachloride, etc., a hydrocarbon type solvent such as benzene,toluene, hexane, heptane, etc., dimethylformamide, dimethyl sulfoxide,etc., the amount of the compound represented by the formula (VI) being 1to 10 molar equivalents, preferably about 1 to 3 molar equivalentsrelative to one mole of the compound of the formula (V') at temperaturesranging from 50° to 200° C., preferably from about 80° to 100° C. forthe period ranging from one to 24 hours, preferably from about 3 to 10hours.

Among the compounds of the formula (I), production of a compound of theformula (1e) ##STR12## wherein symbols are of the same meaning asdefined above can be conducted by subjecting a compound of the formula(Ia), (Ib), (Ic), (Id) or (Ij) to be described later to reaction in asolvent, for example, water or an alcohol type solvent such as methanol,ethanol, propanol, etc. or an ether type solvent such astetrahydrofuran, dioxane, etc., in the presence of a base (e.g. sodiumhydrogencarbonate, potassium hydrogencarbonate, sodium carbonate,potassium carbonate, sodium hydroxide, potassium hydroxide, bariumhydroxide, etc,), an acid (hydrochloric acid, sulfuric acid, nitricacid, etc.) for one to 24 hours, preferably from about 2 to 3 hours attemperatures ranging from 0° to 100° C., preferably from about 20° to50° C.

Among the compounds of the formula (I), a compound of the formula (If)##STR13## wherein Y' stands for optionally substituted carbamoyl groupdefined by Y, and other symbols are of the same meaning as definedabove! can be produced by subjecting the compound of the formula (Ie) tocondensation with amine having the same substituents as those ofoptionally substituted carbamoyl group. For example, in a solventincluding an ether-type one such as diethyl ether, tetrahydrofuran,dioxane, etc., a hydrocarbon type solvent such as benzene, toluene,hexane, heptane, etc., a halogen type solvent such as dichloromethane,chloroform, etc., acetonitrile, dimethylformamide solvent, usually 1 to5 moles of amine having the same substituents as those of the optionallysubstituted carbamoyl group, preferably about 1 to 1.5 moles, relativeto 1 mole of the compound of the formula (Ie). The reaction temperaturesrange from 0° to 100° C., preferably from about 20° to 50° C. Thereaction time ranges from 1 to 24 hours, preferable about 2 to 5 hours.The condensing agent then employed includes diethyl cyanophosphonate,dicyclohexylcarbodiimide, etc., the amount of which being usually 1 to 5moles, preferably 1 to 2 moles, relative to 1 mole of the compound ofthe formula (Ie).

Among the compounds of the formula (I), production of a compound of theformula (Ig) ##STR14## wherein symbols are of the same meaning asdefined above can be conducted by subjecting a compound shown by theformula (Ia), the formula (Ib), the formula (Ic), the formula (Id) or(Ij) described later to reduction with lithium aluminum hydride in anether type solvent such as diethyl ether, tetrahydrofuran, dioxane, etc.Relative to one mole of the compound shown by the formula (Ia), theformula (Ib), the formula (Ic), the formula (Id) or the formula (Ij),lithium aluminum hydride is used in an amount ranging from 0.1 to 3moles, preferably from about 0.3 to 1 mile, and the reaction time rangesfrom 0.5 to 10 hours, preferably from about one to 3 hours. The reactiontemperatures ranges from 0° to 100° C., preferable from about 30° to 70°C. And, the compound shown by the formula (Ig) can also be produced byallowing the compound shown by the formula (Ie) to react with ethylchlorocarbonate, followed by subjecting the reaction mixture toreduction in an ether type solvent such as diethyl ether,tetrahydrofuran, dioxane, etc. with sodium borohydride, lithium aluminumhydride, etc. The reaction between the compound shown by the formula(Ie) and ethyl chlorocarbonate can be conducted in an ether type solventsuch as ethyl ether, tetrahydrofuran, dioxane, etc., a halogen typesolvent such as dichloromethane, chloroform, dichloroethane, etc., or ahydrocarbon type solvent such as hexane, heptane, benzene, toluene,etc., and, when necessary, in the presence of a base (for example, anorganic base such as 4-dimethylaminopyridine, triethylamine,triethylenediamine, tetramethylethylenediamine, etc. or, for example,sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate,potassium carbonate, sodium hydride, potassium hydride) etc. Relative toone mole of the compound shown by the formula (Ie), ethylchlorocarbonate is used usually in an amount ranging from 1 to 5 moles,preferably from about 1 to 2 moles. The reaction temperatures rangesfrom 0° to 100° C., preferably from 20° to 50° C. The reaction timeranges from 0.5 to 10 hours, preferably from about 1 to 3 hours. In thecase of conducting the reduction with sodium borohydride or lithiumaluminum hydride, the reducing agent is employed in an amount rangingfrom 0.1 to 3 moles, preferably from about 0.3 to 1 moles, relative toone mole of the compound obtained by the reaction of ethylchlorocarbonate. The reaction time ranges from 0.5 to 10 hours,preferably from about 1 to 3 hours, and the reaction temperatures rangesfrom 0° to 100° C., preferably from about 30° to 70° C.

Among the compounds of the formula (I), a compound represented by theformula (Ih) ##STR15## wherein Y" stands for the substituted hydroxylgroup defined by Y, and other symbols are of the same meaning as definedabove can be produced by allowing the compound shown by the formula (Ig)to react with a compound represented by the formula (VII), W--R₅ whereinR₅ stands for the substituent of the substituted hydroxyl group definedby Y"; W stands for chlorine, bromine or iodine. More specifically, thecompound shown by the formula (Ig) is allowed to react with the compoundrepresented by the formula (VII) in the presence of a base, for example,an inorganic base such as sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium carbonate, potassium carbonate, etc., anorganic base such as triethylamine, 4-dimethylaminoyridine,triethylenediamine, tetramethyl ethylenediamine, etc., sodium hydride,in a solvent, for example, an alcohol type solvent such as methanol,ethanol, propanol, butanol, etc., an ether type solvent such as diethylether, tetrahydrofuran, dioxane, etc., dimethylformamide, etc. Relativeto one mole of the compound shown by the formula (Ig), the compoundshown by the formula (VII) is used in an amount ranging from 0.5 to 1.5molar equivalent, and, relative to one mole of the compound shown by theformula (Ig), the base to be used ranges from 1 to 5 molar equivalents,preferably from 1 to 2 molar equivalents. The reaction temperaturesranges from 0° to 200° C., preferably from 20° to 100° C., and thereaction time ranges from 0.5 to 24 hours, preferably from about 1 to 3hours.

Among the compounds of the formula (I), among the compounds shown by theformula (Ii) ##STR16## wherein Y"' stands for the optionally substitutedamino group defined by Y, and other symbols are of the same meaning asdefined above, a compound represented by the formula (Ii') ##STR17##wherein symbols are of the same meaning as defined above can be obtainedby, for example, allowing the compound shown by the formula (Ie) toreact with diphenylphosphoryl azide in a solvent in the presence of abase. The solvent to be employed in the reaction between the compoundshown in the formula (Ie) and diphenylphosphoryl azide may be any one solong as it does not hamper the reaction, which is exemplified bydimethylformamide or a halogen type solvent such as dichloromethane,chloroform, dichloroethane, etc., an ether type solvent such as ethylether, tetrahydrofuran, dioxane, etc. As the base to be employed,mention is made of triethylamine, 4-dimethylaminopyridine,triethylenediamine, tetramethylethylenediamine, etc. Relative to 1 moleof the compound shown by the formula (Ie), 1 to 10 molar equivalents,preferably about 1.5 to 3 molar equivalents, of diphenylphosphoryl azideis employed. The reaction temperature ranges from -20° to 50° C.,preferably from 0° to 20° C., and the reaction time ranges from 0.5 to 5hours, preferably from about 1 to 2 hours.

Among the compounds shown by the formula (Ii), the compound representedby the formula (Ii") ##STR18## wherein Y"" stands for the substitutedamino group defined by Y"', and, other symbols are of the same meaningas defined above can be produced by subjecting the compound shown by theformula (Ii') to diazotization with sodium nitrite, followed by heating(reaction temperatures range from 20° to 200° C., preferably from 50° to100° C., and the reaction time ranges from 5 minutes to 2 hours,preferably from about 15 to 30 minutes), by allowing an intermediateshown by the formula (VIII) ##STR19## wherein symbols are of the samemeaning as defined above, to react with a compound shown by H--Y"" (IX)wherein symbols are of the same meaning as defined above!, productionwas accomplished. The compound shown by the formula (VIII) is allowed toreact with a compound shown by the formula (IX) in the presence of abase including an inorganic base such as sodium hydrogencarbonate,potassium hydrogencarbonate, sodium carbonate, potassium carbonate,etc., an organic base such as triethylamine, 4-dimethylaminopyridine,triethylenediamine, tetramethylethylenediamine, etc. or sodium hydridein a solvent, for example, an alcohol type solvent such as methanol,ethanol, propanol, butanol, etc., an ether type solvent such as diethylether, tetrahydrofuran, dioxane, etc., dimethylformamide. Relative toone mole of the compound shown by the formula (VIII), the compound shownby the formula (IX) is used in an amount of 0.5 to 1.5 molarequivalents, and, relative to one mole of the compound shown by theformula (VIII), the base to be employed ranges from 1 to 5 molarequivalents, preferably 1 to 2 molar equivalents, and the reactiontemperatures ranges from 0° to 200° C., preferably from 20° to 100° C.The reaction time ranges from 0.5 to 24 hours, preferably from about 1to 3 hours.

Among the compounds of the formula (I), the compound represented by theformula (Ij) ##STR20## wherein Z"" stands for a carbon chain optionallycontaining a double bond, and other symbols are of the same meaning asdefined above is converted into chlorine by allowing a compound shown bythe formula (Ig') ##STR21## wherein symbols are of the same meaning asdefined above to react with thionyl chloride, phosphorus pentachloride,phosphorus oxychloride, etc. in an amount of, relative to one mole ofthe compound shown by the formula (Ig'), 0.5 to 5 molar equivalents,preferably from 1 to 1.5 molar equivalent, in the absence of a solvent,or in an ether-type solvent such as diethyl ether, tetrahydrofuran,dioxane, etc., a halogen type solvent such as dichloromethane,dichloroethane, chloroform, carbon tetrachloride, etc., at 0° to 200°C., preferably 20° to 50° C., for 0.5 to 5 hours, preferably 1 to 2hours, then, by allowing thus-obtained intermediate to react with sodiumcyanide or potassium cyanide in a solvent such as dimethylformamide,dimethyl sulfoxide, etc, to produce a compound represented by theformula (X) ##STR22## wherein symbols are of the same meaning as definedabove. Relative to one mole of the intermediate obtained by convertingthe hydroxyl group into chlorine, sodium cyanide or potassium cyanide isemployed in an amount of 1 to 10 molar equivalents, preferably 1 to 1.5molar equivalents, and the reaction is allowed to proceed attemperatures ranging from 20° to 200° C., preferably from 50° to 150° C.for 1 to 48 hours, preferably about 5 to 10 hours.

The hydrolysis of thus-obtained compound represented by the formula (X)can be conducted by a per se known method. The hydrolysis can beconducted in the presence of, as a solvent, an alcohol type solvent suchas methanol, ethanol, propanol; acid (e.g. hydrogen chloride, sulfuricacid). The reaction temperature ranges from 30° to 150° C., preferablyfrom 50° to 100° C. The reaction time ranges from 10 minutes to 5 hours,preferably from about 30 minutes to one hour.

While the compound (I) of this invention has a squalene synthetaseinhibiting action or an antifungal action, among the compounds used inthe present invention, there are compounds capable of inhibiting otherenzymes in the pathway of cholesterol biosynthesis. Be the matter as itmay, the compound (I) of this invention inhibits biosynthesis ofcholesterol, which is useful for the prophylaxis or therapy ofhypercholesterolemia or coronary sclerosis of mammals (e.g. mouse, rat,rabbit, dog, cat, cow, pig and human being), and also useful for theprophylaxis or therapy of fungal infection.

Also, the compound (I) is useful for therapy of hyperlipidaemia.

The compound (I) of the present invention can be administered to manorally or non-orally. The orally administrable compositions may be in asolid or liquid form, more specifically tablets (including sugar-coatedtablets and film-coated tablets), pills, granules, powders, capsules(including soft capsule), syrups, emulsions, suspensions or the like.These compositions can be prepared by a per se known method and containcarriers or excipients conventionally used in the field ofpharmaceutical preparation, for example, carriers or excipients such aslactose, starch, sucrose or magnesium stearate for preparing tablets.

The non-orally administrable compositions are exemplified by injectionsand suppositories, and the injections include hypodermic injections,intradermal injections and intramuscular injections. These injectionscan be prepared by a per se known method, more specifically, bysuspending or emulsifying the compound of this invention in a sterilewater or oil conventionally used for preparing injectable compositions.The aqueous liquid to be used for preparation of injections includephysiological saline solution and isotonic solution, and, depending onnecessity, a suitable suspending agent such as sodium carboxymethylcellulose, a non-ionic surfactant or the like may be jointly used. Asthe oil, mention is made of sesame oil, soybean oil, etc., and benzylbenzoate, benzyl alcohol etc. as a solubilizer may be jointly used.Injections thus prepared are, in general, filled in appropriateampoules.

The compound (I) or salts thereof are low in toxicity and can be usedsafely. While the daily dosage varies with the conditions or body weightof the subject patient, kinds of the compounds, administration route,etc., in the case of administering the compound of the present inventionfor the therapy of hypercholesteremia, a daily oral dosage per adulthuman is about 1 to 500 mg, preferably about 10 to 200 mg. Within thisrange, no toxicity is observed at all.

Effective daily dose of the compound (I), when administered to mammals(e.g. man) as a squalene synthetase inhibitor, ranges from about 1 to500 mg, preferably from about 10 to 200 mg in the case of oraladministration, while, in the case of non-oral administration (e.g.injection, suppository), ranges from about 0.1 to 100 mg, preferablyfrom about 1 to 20 mg.

Further, the compound (I) shows a broad anti-bacterial activities asdetermined by the broth or agar dilution method.

Effective daily dose of the compound (I) for the antifungal purpose tobe administered to mammals (e.g. man, etc.) ranges from about 0.1 to 100mg, preferably from about 1 to 50 mg in the case of oral administration,while in the case of non-oral administration (e.g. injection,suppository, etc.) it ranges from about 0.1 to 100 mg, preferably from 1to 50 mg.

EXAMPLES

The following examples, formulation examples and test examples areintended to illustrate the present invention in further detail andshould by no means be construed as defining the metes and bounds of theinvention.

In the following description, two types of racemic diastereomers areobtained depending of the kinds of compounds, which is due to thepresence of asymmetric carbon atoms at 3- and 5-positions. Isomers inwhich the substituents at 3- and 5-positions are oriented in the samedirection relative to the face of 7-membered ring are named cis-isomers,while those in which the substituents at 3- and 5-positions are orientedin the adverse directions to each other are named trans-isomers.Further, compounds containing asymmetric carbons, for example,(3RS,5RS,αSR) means a mixture of (3R,5R,αS) and (3S,5S,αR).

Example 1(3RS,5RS,αSR)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester, and(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester ##STR23## (1) 5-Chloro-α-(2-chlorophenyl)-2-N-(trans-2,3-epoxy-4-ethoxycarbonyl)butyryl-N-isopropyl!aminobenzylalcohol

To a solution of DL-trans-2,3-epoxysuccinic acid monoethyl ester (3.1 g)in methylene chloride (90 ml) was added(dichloromethylene)dimethyliminium chloride (3.14 g) under ice-cooling,and the mixture was stirred for one hour. To the reaction mixture wereadded 5-chloro-α-(2-chlorophenyl)-2-isopropylaminobenzyl alcohol (4.0 g)and sodium hydrogencarbonate (5.42 g), which was stirred for one hourunder ice-cooling. The reaction mixture was washed with water and driedover anhydrous magnesium sulfate, followed by distilling off the solventunder reduced pressure. The residue was purified by means of a silicagel column chromatography (hexane:ethyl acetate=2:1) to give5-chloro-α-(2-chlorophenyl)-2-N-(trans-2,3-epoxy-4-ethoxycarbonyl)butyryl-N-isopropyl!aminobenzylalcohol. (5.6 g) as crystals, m.p. 143°-146° C.

Elemental Analysis for C₂₂ H₂₃ Cl₂ NO₅ : Calcd.: C, 58.42; H, 5.13; N,3.10 Found: C, 58.55; H, 5.31; N, 3.12

(2)(3RS,5RS,αSR)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester and(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester

In ethanol (200 ml) was dissolved 5-chloro-α-(2-chlorophenyl)-2-N-(trans-2,3-epoxy-4-ethoxycarbonyl)butyryl-N-isopropyl!aminobenzylalcohol(10.0 g). To the solution was added potassium carbonate (3.06 g), whichwas stirred overnight at room temperature. The solvent was distilled offunder reduced pressure. The residue was subjected to extraction by theaddition of water (200 ml) and ethyl acetate (300 ml). The ethyl acetatelayer was washed with water, which was dried over anhydrous magnesiumsulfate, then the solvent was distilled off under reduced pressure. Theresidue was purified by means of a silica gel column chromatography(hexane:ethyl acetate=2:1) to give7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester (7.2 g, 72%) as a mixture (1:1) of (3RS,5RS,αSR)compound and (3RS,5SR,αSR) compound. This mixture was recrystallizedtwice from hexane--ethyl acetate to afford(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester (1.75 g) as prisms, m.p. 188°-189° C.

Mass spectrum (m/e): 451 (M⁺)

Elemental Analysis for C₂₂ H₂₃ Cl₂ NO₅ : Calcd.: C, 58.42; H, 5.13; N,3.10 Found: C, 58.63; H, 5.31; N, 3.12

Filtrates after the recrystallizations were combined, which wascrystallized from hexane--ethyl acetate. Resulting crystals wererecrystallized twice from hexane--ethyl acetate to afford(3RS,5RS,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester (1.2 g) as prisms, m.p. 141°-142° C.

Mass spectrum (m/e): 451 (M⁺)

Elemental Analysis for C₂₂ H₂₃ Cl₂ NO₅ : Calcd.: C, 58.42; H, 5.13; N,3.10 Found: C, 58.55; H, 5.02; N, 3.11

Example 2(3RS,5RS,αRS)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester and(3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester ##STR24## (1) 5-Chloro-α-(2-chlorophenyl)-2-N-(cis-2,3-epoxy-4-ethoxycarbonyl)butyryl-N-isopropyl!aminobenzylalcohol

To a solution of methylene chloride (200 ml) of DL-cis-2,3-epoxysuccinic acid monoethyl ester (10.1 g) was added(dichloromethylene)dimethyliminium chloride (10.2 g) under ice-cooling,and the mixture was stirred for one hour. To the reaction mixture wereadded 5-chloro-α-(2-chlorophenyl)-2-isopropylamimobenzyl alcohol (15.0g) and sodium hydrogencarbonate (20.3 g), which was stirred for one hourunder ice-cooling. The reaction mixture was washed with water, which wasdried over anhydrous magnesium sulfate, followed by distilling off thesolvent under reduced pressure. The residue was purified by means of asilica gel column chromatography (hexane:ethyl acetate=2:1) to give5-chloro-α-(2-chlorophenyl)-2-N-(cis-2,3-epoxy-4-ethoxycarbonyl)butyryl-N-isopropyl!aminobenzylalcohol (17.9 g) as crystals, m.p. 139°-141° C.

Elemental Analysis for C₂₂ H₂₃ Cl₂ NO₅ : Calcd.: C, 58.42; H, 5.13; N,3.10 Found: C, 58.64; H, 5.13; N, 3.01

(2)(3RS,5RS,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester and(3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester

In ethanol (150 ml) was dissolved 5-chloro-α-(2-chlorophenyl)-2-N-(cis-2,3-epoxy-4-ethoxycarbonyl)butyryl-N-isopropyl!aminobenzylalcohol(15.0 g). To the solution was added potassium carbonate (4.6 g), whichwas stirred overnight at room temperature. The solvent was distilled offunder reduced pressure. The residue was subjected to extraction by theaddition of water (200 ml) and ethyl acetate (300 ml). The ethyl acetatelayer was washed with water and dried over anhydrous magnesium sulfate,followed by distilling off the solvent under reduced pressure. Theresidue was purified by means of a silica gel column chromatography(hexane:ethyl acetate=2:1) to give7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester (9.0 g, 60%) as a mixture of about 1:1 of (3RS,5RS,αSR)compound and (3RS,5SR,αSR).

IR ν_(max) ^(neat) cm⁻¹ : 3440(OH); 1735, 1665(C═O)

Mass spectrum (m/e): 451 (M⁺)

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.26(3H,t,J=7.2 Hz), 1.28(3H,d,J=7.2Hz), 1.55(3H,d,J=7.2 Hz), 4.0-4.1(1H,m), 4.19(2H,q,J=7.2 Hz),4.39(1H,d,J=2.8 Hz), 4.50(1H,dd,J=8.6 Hz,2.8 Hz), 4.7-4.9(1H,m),5.18(1H,d,J=8.6 Hz), 6.01(1H,s), 6.53(1H,d,J=2.4 Hz), 7.2-7.8(7H,m)

Example 37-Chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester ##STR25## (1) 5-Chloro-α-(2-chlorophenyl)-2-N-(trans-2,3-epoxy-4-ethoxycarbonyl)butyryl-N-isobutyl!aminobenzylalcohol

Using 5-chloro-α-(2-chlorophenyl)-2-isobutylamino benzylalcohol (10 g),substantially the same procedure as in Example 1-(1) was taken to givean oily compound (14.0 g).

¹ H-NMR (CDCl₃) δ: 0.75-1.05(6H,m), 1.15-1.4(3H,m), 1.7-2.0(1H,m),2.7-3.3(2H,m), 3.3-3.9(2H,m), 4.0-4.45(3H,m), 6.1-6.4(1H,m),7.0-7.8(7H,m)

(2)7-Chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester

In ethanol (150 ml) were added 5-chloro-α-(2-chlorophenyl)-2-N-(trans-2,3-epoxy-4-ethoxycarbonyl)butyryl-N-isobutyl!aminobenzylalcohol (13.0 g) and potassium carbonate (3.85 g). The mixture wasstirred overnight at room temperature. The solvent was distilled off.The residue was dissolved in ethyl acetate. The solution was washed withwater, which was then dried over anhydrous magnesium sulfate. Thesolvent was distilled off, and the residue was purified by means of asilica gel column chromatography as colorless crystals (7.0 g).

Elemental Analysis for C₂₃ H₂₅ Cl₂ NO₅ : Calcd.: C, 59.24; H, 5.40; N,3.00 Found: C, 59.14; H, 5.37; N, 2.98

¹ H-NMR (CDCl₃) δ: 0.7-1.1(6H,m), 1.2-1.4(5H,m), 1.7-2.1(1H,m),3.35-4.0(2H,m), 4.0-4.8(5H,m), 6.15 and 6.19(1H,each s), 6.55 and6.96(1H,each d, J=2.4 Hz), 7.15-7.8(6H,m)

Example 47-Chloro-5-(2-chlorophenyl)-1-propyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester ##STR26##

Using 5-chloro-α-(2-chlorophenyl)-2-propylamino benzyl alcohol,production was performed by substantially the same procedures as inExample 1-(1) and Example 3-(2).

(1) 5-Chloro-α-(2-chlorophenyl)-2-N-(trans-2,3-epoxy-4-ethoxycarbonyl)butyryl-N-propyl!aminobenzyl alcoholan oily compound

¹ H-NMR(CDCl₃) δ: 0.75-1.05(3H,m), 1.1-1.8(5H,m), 2.6-3.9(4H,m),4.0-4.5(3H,m), 6.1-6.4(1H,m), 6.9-7.9(7H,m)

(2)7-Chloro-5-(2-chlorophenyl)-1-propyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester

Colorless crystals

Elemental Analysis for C₂₂ H₂₃ Cl₂ NO₅ : Calcd.: C, 58.42; H, 5.12; N,3.10 Found: C, 58.40; H, 5.23; N, 3.01

¹ H-NMR (CDCl₃) δ: 0.7-1.05(3H,m), 1.15-1.4(3H,m), 1.45-1.8(2H,m),3.4-3.9(2H,m), 4.0-4.7(4H,m), 6.08 and 6.10(1H,each s), 6.5-7.8(7H,m)

Example 5(3RS,5SR,αSR)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ##STR27##

In ethanol (8 ml) was dissolved(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester (0.3 g) obtained in Example 1. To the solution wasadded 1N sodium hydroxide (2 ml), and the mixture was left standing for20 minutes at room temperature. To the resultant mixture was added 1Nhydrochloric acid (50 ml) to make the solution acid, followed byextraction with ethyl acetate (50 ml). The extract solution was washedwith water, dried over anhydrous magnesium sulfate, then the solvent wasdistilled off under reduced pressure to give(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid (0.26 g) as prisms, m.p. 245°-247° C. (decomp.).

Elemental Analysis for C₂₀ H₁₉ Cl₂ NO₅ : Calcd.: C, 56.62; H, 4.51; N,3.30 Found: C, 56.47; H, 4.40; N, 3.32

Example 6(3RS,5RS,αSR)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ##STR28##

(3RS,5RS,αSR)-7-Chloro-5-(2-chlorophenyl-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester (0.3 g) obtained in Example 1 was subjected tosubstantially the same procedure as in Example 5 to afford 0.26 g ofcolorless crystals, m.p. 237°-239° C. (decomp.).

Elemental Analysis for C₂₀ H₁₉ Cl₂ NO₅ : Calcd.: C, 56.62; H, 4.51; N,3.30 Found: C, 56.83; H, 4.62; N, 3.34

Example 7(3RS,5RS,αRS)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid and,(3RS,5SR,αRS)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ##STR29##

A mixture (4.5 g) of(3RS,5RS,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester and(3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester obtained in Example 2 was dissolved in ethanol (50 ml).To the solution was added 1N sodium hydroxide (30 ml), and mixture wasstirred for 30 minutes at room temperature. To the resultant mixture wasadded 1N hydrochloric acid (100 ml) to make the solution acid, which wasextracted with ethyl acetate (200 ml). The extract solution was washedwith water, dried over anhydrous magnesium sulfate, then the solvent wasdistilled off under reduced pressure. The residue was crystallized fromhexane-ethyl acetate to give a mixture (3.3 g) of(3RS,5RS,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid and(3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid. This mixture was recrystallized twice from hexane-ethanol to give(3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid (0.94 g) as plates, m.p. 226°-230° C. (decomp.).

Elemental Analysis for C₂₀ H₁₉ Cl₂ NO₅.EtOH: Calcd.: C, 56.18; H, 5.36;N, 2.98 Found: C, 56.12; H, 5.41; N, 2.96

Filtrates after recrystallizations were combined, which was subjected todistillation under reduced pressure to leave crystals, which wererecrystallized twice from hexane-ethanol to give(3RS,5RS,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid (0.49 g) as plates, m.p. 220°-224° C. (decomp.).

Elemental Analysis for C₂₀ H₁₉ Cl₂ NO₅ : Calcd.: C, 56.62; H, 4.51; N,3.30 Found: C, 56.80; H, 4.80; N, 3.24

Example 8(3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester ##STR30##

A mixture of(3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid (0.15 g) obtained in Example 7, p-toluenesulfonic acid monohydrate(6 mg) and ethanol (20 ml) was heated for 10 hours under reflux. Ethanolwas distilled off under reduced pressure. To the residue were addedwater (50 ml) and ethyl acetate (50 ml). The organic layer was washedwith an aqueous solution of sodium hydrogencarbonate, dried overanhydrous magnesium sulfate, followed by distilling off the solventunder reduced pressure to leave(3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester (95 mg) as prisms, m.p. 126°-128° C.

Elemental Analysis for C₂₂ H₂₃ Cl₂ NO₅ : Calcd.: C, 58.42; H, 5.13; N,3.10 Found: C, 58.31; H, 5.15; N, 3.15

Example 9(3RS,5RS,αRS)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester ##STR31##

A mixture of(3RS,5RS,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid (0.15 g) obtained in Example 7, p-toluenesulfonic acid monohydrate(7 mg) and ethanol (20 ml) was heated for 24 hours under reflux. Ethanolwas distilled off under reduced pressure. The residue was dissolved in amixture of water (50 ml) and ethyl acetate (50 ml). The organic layerwas washed with an aqueous solution of sodium hydrogencarbonate, whichwas dried over anhydrous magnesium sulfate, then the solvent was wasdistilled off under reduced pressure to leave(3RS,5RS,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester (0.14 g) as prisms, m.p. 119°-120° C.

Elemental Analysis for C₂₂ H₂₃ Cl₂ NO₅ : Calcd.: C, 58.42; H, 5.13; N,3.10 Found: C, 58.53; H, 5.18; N, 3.26

Example 10(Z)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid ethyl ester and,(E)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid ethyl ester ##STR32## (1)(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-4,1-benzoxazepine-3-α-(methanesulfonyloxy)aceticacid ethyl ester

In ethyl acetate (30 ml) was dissolved(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-4,1-benzoxazepine-3-glycolicacid ethyl ester (0.8 g) obtained in Example 1. To the solution wereadded methanesulfonyl chloride (0.18 ml) and triethylamine (0.32 ml)under ice-cooling, and the mixture was stirred for one hour at roomtemperature. The reaction mixture was washed with water, dried overanhydrous magnesium sulfate, then the solvent was distilled off underreduced pressure. The residue was purified by means of a silica gelcolumn chromatography (hexane:methylene chloride:ethyl acetate=10:5:1)to afford(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-4,1-benzoxazepine-3-α-(methanesulfonyloxy)aceticacid ethyl ester (0.82 g) as prisms, m.p. 159°-160° C.

Elemental Analysis for C₂₃ H₂₅ Cl₂ NO₇ S; Calcd.: C, 52.08; H, 4.75; N,2.64 Found: C, 52.25; H, 4.80; N, 2.74

(2)(Z)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid ethyl ester and,(E)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid ethyl ester

In methanol (10 ml) was dissolved propionic acid (0.23 g), to which wasadded cesium carbonate (0.34 g), and the mixture was stirred for 30minutes at room temperature. Methanol was distilled off under reducedpressure. To the residue was added toluene (10 ml), which was againsubjected to distillation under reduced pressure to leave cesiumpropionate as a powdery product. A mixture of this product,(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-4,1-benzoxazepine-3-α-(methanesulfonyloxy)acetic acid ethyl ester (1.0 g) and N,N-dimethylformamide (10 ml) wasstirred for 2 hours at 80° C. After adding water (50 ml), the mixturewas extracted with ethyl acetate (100 ml). The ethyl acetate layer waswashed with 1N hydrochloric acid and an aqueous solution of sodiumhydrogencarbonate, which was then dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by means of a silica gel column chromatography(hexane:ethyl acetate=10:1-5:1). From the first fraction,(Z)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid ethyl ester (0.31 g) as prisms, m.p. 194°-195° C.

Mass spectrum (m/e): 433 (M⁺)

Elemental Analysis for C₂₂ H₂₁ Cl₂ NO₄ : Calcd.: C, 60.84; H, 4.87; N,3.22 Found: C, 60.76; H, 4.99; N, 3.32

And, from the second fraction,(E)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid ethyl ester (0.13 g) was obtained as prisms, m.p. 143°-144° C.

Mass spectrum (m/e): 433 (M⁺)

Elemental Analysis for C₂₂ H₂₁ Cl₂ NO₄ : Calcd.: C, 60.84; H, 4.87; N,3.22 Found: C, 60.59; H, 4.84; N, 3.30

In like manner,(3RS,5RS,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-4,1-benzoxazepine-3-α-(methanesulfonyloxy)aceticacid ethyl ester (1.0 g) was allowed to react with cesium propionate,followed by purification by means of a silica gel column chromatography.From the first fraction,(Z)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid ethyl ester (0.335 g) was obtained as prisms. And, from the secondfraction, was obtained(E)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid ethyl ester (0.17 g) as prisms.

(3)(3RS,5RS,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-4,1-benzoxazepine-3-α-(methanesulfonyloxy)aceticacid ethyl ester

In ethyl acetate (30 ml) was dissolved(3RS,5RS,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-4,1-benzoxazepine-3-glycolicacid ethyl ester (0.6 g). To the solution were added methanesulfonylchloride (0.13 ml) and triethylamine (0.24 ml) under ice-cooling. Themixture was stirred for one hour at room temperature. The reactionmixture was washed with water, dried over anhydrous magnesium sulfate,followed by distilling off the solvent under reduced pressure. Theresidue was purified by means of a silica gel column chromatography(hexane: methylene chloride: ethyl acetate=10:5:1) to give(3RS,5RS,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-4,1-benzoxazepine-3-α-(methanesulfonyloxy)aceticacid ethyl ester (0.63 g) as prisms, m.p. 143°-144° C.

Elemental Analysis for C₂₃ H₂₅ Cl₂ NO₇ S: Calcd.: C, 52.08; H, 4.75; N,2.64 Found: C, 52.38; H, 4.89; N, 2.77

Example 11(Z)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid ##STR33##

To the solution of(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid ethyl ester (0.3 g) obtained in example 10 in methanol (30 ml) wasadded an aqueous solution of sodium hydroxide (5 ml). The solution wasstirred for one hour at 50° C. Methanol was distilled off under reducedpressure. To the residue were added 1N hydrochloric acid (50 ml) andethyl acetate (100 ml). The ethyl acetate layer was washed with waterand dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure to leave(Z)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-3-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)aceticacid (0.26 g) as prisms, m.p. 234°-239° C.

IR ν_(max) ^(KBr) cm⁻¹ : 1670, 1655 (C═O, C═C)

Elemental Analysis for C₂₀ H₁₇ Cl₂ NO₄ : Calcd.: C, 59.13; H, 4.22; N,3.45 Found: C, 59.02; H, 4.21; N, 3.37

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.31(3H,d,J=7.0 Hz), 1.61(3H,d,J=7.0Hz), 4.7-4.9(1H,m), 5.48(1H,s), 6.54(1H,s), 6.57(1H,d,J=2.2 Hz),7.3-7.6(5H,m), 8.05(1H,d,J=7.8 Hz)

Example 12(E)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3α)-aceticacid ##STR34##

In methanol (20 ml) was dissolved(E)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid ethyl ester (0.16 g) obtained in Example 10. To the solution wasadded an aqueous solution of sodium hydroxide (5 ml). The mixture wasstirred for one hour at 50° C. Methanol was distilled off under reducedpressure. The residue was subjected to extraction by the addition of 1Nhydrochloric acid (50 ml) and ethyl acetate (100 ml). The ethyl acetatelayer was washed with water, dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure to leave(E)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-aceticacid (0.135 g) as prisms, m.p. 209°-214° C.

IR ν_(max) ^(KBr) cm⁻¹ : 1720, 1650, 1630 (C═O,C═C)

Elemental Analysis for C₂₀ H₁₇ Cl₂ NO₄ : Calcd.: C, 59.13; H, 4.22; N,3.45 Found: C, 58.97; H, 4.24; N, 3.42

¹ H-NMR spectrum (200 MHz,CDCl₃) δ: 1.34(3H,d,J=7.0 Hz), 1.62(3H,d,J=7.0Hz), 4.8-5.0(1H,m), 5.41(1H,s), 6.51(1H,s), 6.54(1H,d,J=1.8 Hz),7.3-7.6(5H,m), 7.78(1H,d,J=7.0 Hz)

Example 13

By substantially the same procedures as in Example 10, Example 12 andExample 13, compounds listed in Table 1! were obtained.

                                      TABLE 1                                     __________________________________________________________________________     ##STR35##                                                                    Compd.        = bond                                                                            m.p. Molecular                                                                            Elemental Analysis (Found)                      No. R.sub.1                                                                              R.sub.2                                                                          steric                                                                            (°C.)                                                                       Formula                                                                              C   H   N                                       __________________________________________________________________________    1   CH.sub.2 CH.sub.2 CH.sub.3                                                           C.sub.2 H.sub.5                                                                  Z   171-172                                                                            C.sub.22 H.sub.21 Cl.sub.2 NO.sub.4                                                  60.84                                                                             4.87                                                                              3.22                                                                  (60.65                                                                            4.73                                                                              3.15)                                   2   CH.sub.2 CH.sub.2 CH.sub.3                                                           C.sub.2 H.sub.6                                                                  E   114-115                                                                            C.sub.22 H.sub.21 Cl.sub.2 NO.sub.4                                                  60.84                                                                             4.87                                                                              3.22                                                                  (60.85                                                                            5.17                                                                              3.13)                                   3   CH.sub.2 CH.sub.2 CH.sub.3                                                           H  Z   208-210                                                                            C.sub.20 H.sub.17 Cl.sub.2 NO.sub.4                                                  59.13                                                                             4.22                                                                              3.45                                                      (decomp)    (59.20                                                                            4.39                                                                              3.32)                                   4   CH.sub.2 CH.sub.2 CH.sub.3                                                           H  E   192-194                                                                            C.sub.20 H.sub.17 Cl.sub.2 NO.sub.4                                                  59.13                                                                             4.22                                                                              3.45                                                      (decomp.)   (58.88                                                                            4.34                                                                              3.27)                                   5   CH.sub.2 CH(CH.sub.3).sub.2                                                          C.sub.2 H.sub.5                                                                  Z   181-182                                                                            C.sub.23 H.sub.23 Cl.sub.2 NO.sub.4                                                  61.62                                                                             5.17                                                                              3.12                                                                  (61.54                                                                            5.30                                                                              3.09)                                   6   CH.sub.2 CH(CH.sub.3).sub.2                                                          C.sub.2 H.sub.5                                                                  E   oily C.sub.23 H.sub.23 Cl.sub.2 NO.sub.4                                                  (a)                                             7   CH.sub.2 CH(CH.sub.3).sub.2                                                          H  Z   236-238                                                                            C.sub.21 H.sub.19 Cl.sub.2 NO.sub.4                                                  60.01                                                                             4.56                                                                              3.33                                                      (decomp.)   (60.16                                                                            4.56                                                                              3.50)                                   8   CH.sub.2 CH(CH.sub.3).sub.2                                                          H  E   207-209                                                                            C.sub.21 H.sub.19 Cl.sub.2 NO.sub.4                                                  60.01                                                                             4.56                                                                              3.33                                                      (decomp.)   (59.95                                                                            4.65                                                                              3.45)                                   __________________________________________________________________________     (a).sup.1 H-NMR(CDCl.sub.3)δ: 0.95(3H, d, J=6.6Hz), 1.07(3H, d,         J=6.6Hz), 1.9-2.2(1H, m), 3.57(1H, dd, J=14.0, 5.8Hz), 4.0-4.25(2H, m),       4.37(1H, dd, J=14.0, 8.6Hz), 5.44(1H, s), 6.54(1H, d, J=1.8Hz), 6.57(1H,      s), 7.3-7.9(6H, m)                                                       

Example 14(3RS,5SR,αRS)-7-Chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid ethyl ester and(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid ethyl ester ##STR36## (1)3,5-trans-7-Chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethanol

To a solution of tetrahydrofuran (30 ml) of3,5-trans-7-chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (3.0 g) and N-methylmorpholine (0.97 ml) was added ethylchloroformate (0.84 ml) at -10° C. The mixture was stirred for 10minutes. To the reaction mixture was added sodium borohydride (0.93 g),and the mixture was stirred for 10 minutes at room temperature. Thesolvent was distilled off, and the residue was made acid with dilutehydrochloric acid, which was extracted with ethyl acetate. The extractsolution was dried over anhydrous magnesium sulfate. The solvent wasdistilled off. The residue was purified by means of a silica gel columnchromatography to afford colorless crystals (2.27 g), m.p. 184°-186° C.

Elemental Analysis for C₂₀ H₂₁ Cl₂ NO₃ : Calcd.: C, 60.92; H, 5.37; N,3.55 Found: C, 61.03; H, 5.27; N, 3.53

(2)3,5-trans-7-Chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehyde

To a solution of oxalyl chloride (0.60 ml) in dichloromethane (5 ml) wasadded a solution of dimethylsulfoxide (0.53 ml) in dichloromethane (2ml) dropwise at -65° C., taking 5 minutes. The mixture was stirred for 5minutes. To the reaction mixture was added dropwise a solution of thecompound (2.1 g) obtained in (1), then, the mixture was stirred for 15minutes at -65° C. To the mixture was added triethylamine (2.9 ml) atthe same temperature, then the mixture was stirred for 10 minutes atroom temperature. To the reaction mixture was added 1N hydrochloric acid(50 ml). The organic layer was dried over anhydrous magnesium sulfate.The solvent was distilled off. The residue was recrystallized fromhexane/dichloromethane to give 1.64 g of colorless crystals, m.p.157°-159° C.

Elemental Analysis for C₂₀ H₁₉ Cl₂ NO₃.0.4H₂ O: Calcd.: C, 60.13; H,5.00; N, 3.51 Found: C, 60.24; H, 4.86; N, 3.57

(3)(3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehydecyanohydrin,(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehydecyanohydrine

A mixture of the compound (1.5 g) obtained in (2), acetone cyanohydrin(5 ml) and triethylamine (0.1 ml) was stirred for 30 minutes at roomtemperature. To the reaction mixture was added ethyl ether, which waswashed with water and dried over anhydrous magnesium sulfate. Thesolvent was distilled off, and the residue was purified by means of asilica gel column chromatography. From the first fraction, (3RS,5SR,αRS)derivative was obtained as colorless crystals (0.42 g), m.p. 159°-162°C.

Elemental Analysis for C₂₁ H₂₀ Cl₂ N₂ O₃ : Calcd.: C, 60.15; H, 4.81; N,6.68 Found: C, 60.18; H, 4.97; N, 6.54

From the second fraction, (3RS,5SR,αSR) derivative was obtained ascolorless crystals (0.61 g), m.p. 177°-180° C.

Elemental Analysis for C₂₁ H₂₀ Cl₂ N₂ O₃ : Calcd.: C, 60.15; H, 4.81; N,6.68 Found: C, 59.94; H, 4.76; N, 6.52

(4)(3RS,5SR,αRS)-7-Chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid ethyl ester

In a mixture solvent consisting of ethanol (10 ml) and dioxane solutionof 4N hydrogen chloride (10 ml) was dissolved the (3RS,5SR,αRS)derivative (0.40 g) obtained in (3). The solution was stirred for 30minutes under heating. The solvent was distilled off, and the residuewas dissolved in acetic acid ethyl ester. The solution was washed with asaturated aqueous solution of sodium hydrogencarbonate, which was driedover anhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified by means of a silica gel column chromatography togive 0.40 g of an oily compound.

¹ H-NMR(CDCl₃) δ: 0.97(3H,t,J=7.4 Hz), 1.27(3H,t,7,2 Hz),1.5-1.9(1H,d,J=6.2 Hz), 3.4-3.6(1H,m), 4.0-4.5(4H,m), 6.08(1H,s),6.52(1H,d,J=2.4 Hz), 7.2-7.8(6H,m) (5)(3RS,5SR,αSR)-7-Chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid ethyl ester

From the (3RS,5SR,αSR) derivative obtained in (3) (0.45 g), an oilycompound (0.45 g) was obtained by substantially the same procedure as in(4).

¹ H-NMR(CDCl₃) δ: 0.97(3H,t,J=7.4 Hz), 1.18(3H,t,J=7.1 Hz),1.5-1.9(2H,m), 2.3-2.5(2H,m), 3.18(1H,d,J=4.6 Hz), 3.4-3.6(1H,m),4.0-4.5(4H,m), 6.03(1H,s), 6.50(1H,d,J=2.4 Hz), 7.2-7.8(6H,m)

Example 15(3RS,5SR,αRS)-7-Chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid ##STR37##

In ethanol (3 ml) was dissolved the compound (0.2 g) obtained in Example14-(4). To the solution was added 1N aqueous solution of sodiumhydroxide (1 ml), and the mixture was stirred for 15 minutes at roomtemperature. To the reaction mixture was added 1N hydrochloric acid (50ml), and the mixture was extracted with acetic acid ethyl ester. Theextract was washed with water and dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue wasrecrystallized from hexane to give colorless crystals (0.15 g), m.p.210°-214° C.

Elemental Analysis for C₂₁ H₂₁ Cl₂ NO₅ : Calcd.: C, 57.55; H, 4.83; N,3.20 Found: C, 57.38; H, 4.93; N, 2.90

Example 16(3RS,5SR,αSR)-7-Chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionicacid ##STR38##

From the compound (0.2 g) obtained in-Example 14-(5), 0.16 g of acolorless crystalline product was obtained by substantially the sameprocedure as in Example 15, m.p. 138°-141° C.

Elemental Analysis for C₂₁ H₂₁ Cl₂ NO₅ : Calcd.: C, 57.55; H, 4.83; N,3.20 Found: C, 57.27; H, 5.03; N, 2.95

Example 17

By substantially the same procedures as in Example 14 and Example 15,compounds set forth in Table 2! and Table 3! were obtained.

                                      TABLE 2                                     __________________________________________________________________________     ##STR39##                                                                    Compd.          Steric  m.p. Molecular                                                                             Elemental Analysis (Found)               No. R.sub.1                                                                              R.sub.2                                                                            Configuration                                                                         (°C.)                                                                       Formula C   H   N                                __________________________________________________________________________    inter-                                                                            CH(CH.sub.3).sub.2                                                                   CN   (3RS, 5SR, αRS)                                                                 142-145                                                                            C.sub.21 H.sub.20 Cl.sub.2 N.sub.2 O.sub.3                                            60.15                                                                             4.81                                                                              6.68                             mediate                              (60.16                                                                            4.96                                                                              6.63)                            inter-                                                                            CH(CH.sub.3).sub.2                                                                   CN   (3RS, 5SR, αSR)                                                                 181-184                                                                            C.sub.21 H.sub.20 Cl.sub.2 N.sub.2 O.sub.3                                            60.15                                                                             4.81                                                                              6.68                             mediate                              (59.97                                                                            4.90                                                                              6.64)                            inter-                                                                            CH.sub.2 CH(CH.sub.3).sub.2                                                          CN   (3RS, 5SR, αRS)                                                                 169-172                                                                            C.sub.22 H.sub.22 Cl.sub.2 N.sub.2 O.sub.3                                            60.98                                                                             5.12                                                                              6.46                             mediate                              (61.06                                                                            5.10                                                                              6.38)                            inter-                                                                            CH.sub.2 CH(CH.sub.3).sub.2                                                          CN   (3RS, 5SR, αSR)                                                                 178-181                                                                            C.sub.22 H.sub.22 Cl.sub.2 N.sub.2 O.sub.3                                            60.98                                                                             5.12                                                                              6.46                             mediate                              (61.15                                                                            5.01                                                                              6.52)                            1   CH(CH.sub.3).sub.2                                                                   COOC.sub.2 H.sub.5                                                                 (3RS, 5SR, αRS)                                                                 oily a                                                2   CH(CH.sub.3).sub.2                                                                   COOC.sub.2 H.sub.5                                                                 (3RS, 5SR, αSR)                                                                 oily b                                                3   CH.sub.2 CH(CH.sub.3).sub.2                                                          COOC.sub.2 H.sub.5                                                                 (3RS, 5SR, αRS)                                                                 oily c                                                4   CH.sub.2 CH(CH.sub.3).sub.2                                                          COOC.sub.2 H.sub.5                                                                 (3RS, 5SR, αSR)                                                                 oily d                                                5   CH(CH.sub.3).sub.2                                                                   COOH (3RS, 5SR, αRS)                                                                 197-201                                                                            C.sub.21 H.sub.21 Cl.sub.2 NO.sub.5                                                   57.55                                                                             4.83                                                                              3.20                                                                  (57.61                                                                            5.03                                                                              3.13)                            __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________                                           Elemental Analysis                     Compd.         Steric  m.p.            (Found)                                No. R.sub.1                                                                              R.sub.2                                                                           Configuration                                                                         (°C.)                                                                       Molecular Formula                                                                        C   H  N                               __________________________________________________________________________    6   CH(CH.sub.3).sub.2                                                                   COOH                                                                              (3RS, 5SR, αSR)                                                                 204-208                                                                            C.sub.21 H.sub.21 Cl.sub.2 NO.sub.5                                                       57.55                                                                            4.83                                                                             3.20                                                                   (57.63                                                                            4.96                                                                             3.36)                           7   CH.sub.2 CH(CH.sub.3).sub.2                                                          COOH                                                                              (3RS, 5SR, αRS)                                                                 209-211                                                                            C.sub.22 H.sub.23 Cl.sub.2 NO.sub.5 0.2C.sub.6                                 H.sub.14   59.34                                                                            5.54                                                                             2.98                                                                   (59.38                                                                            5.67                                                                             3.09)                           8   CH.sub.2 CH(CH.sub.3).sub.2                                                          COOH                                                                              (3RS, 5SR, αSR)                                                                 101-105                                                                            C.sub.22 H.sub.23 Cl.sub.2 NO.sub.5                                                       58.42                                                                            5.13                                                                             3.10                                                                   (58.46                                                                            5.38                                                                             3.08)                           __________________________________________________________________________

a: ¹ H-NMR(CDCl₃) δ: 1.27(3H,t,J=7.2 Hz), 1.30(3H,d,j=7.0 Hz),1.56(3H,d,J=6.8 Hz), 2.01 (1H,ddd,J=14.4,10.4,4.0 Hz), 2.50(1H,ddd,J=14.4,9.0,3.0 Hz), 2.99(1H,d,J=6.4 Hz), 4.22 (2H,q,J=7.2 Hz),4.1-4.3(1H,m), 4.35-4.5(1H,m), 4.7-5.0(1H,m), 6.05(1H,s),6.51(1H,d,J=2.4 Hz), 7.2-7.6 (6H,m)

b. ¹ H-NMR(CDCl₃) δ: 1.18(3H,t,J=7.1 Hz), 1.29(3H,d,J=7.0 Hz),1.56(3H,d,J=6.8 Hz), 2.3-2.45(2H,m), 3.22(1H,d,J=4.5 Hz), 4.0-4.3(3H,m),4.3-4.4(1H,m), 4.7-4.95(1H,m), 6.00(1H,s), 6.49(1H,d,J=2.2 Hz),7.2-7.8(6H,m)

c: ¹ H-NMR(CDCL₃) δ: 0.93(3H,d,J=6.8 Hz), 1.03(3H,d,J=6.6 Hz),1.26(3H,t,J=7.1 Hz), 1.85-2.1(1H,m), 2.52(1H,ddd,J=14.3,9.2,2.6 Hz),2.9-3.05(1H,m), 3.42(1H,dd,J=13.8,5.4 Hz), 4.05-4.55(4H,m), 6.18(1H,s),6.52(1H,d,J=2.3 Hz), 7.2-7.85(6H,m)

d: ¹ H-NMR(CDCl₃) δ: 0.93(3H,d,J=6.8 Hz), 1.04(3H,d,J=6.6 Hz),1.18(3H,t,J=7.1 Hz), 1.85-2.1(1H,m), 2.25-2.5(2H,m), 3.1-3.3(1H,br),3.43(1H,dd,J=13.6,5.4 Hz), 4.0-4.45(5H,m), 6.14(1H,s), 6.51(1H,d,J=2.2Hz),7,2-7.8(6H,m)

Physico-chemical properties of the intermediates

(1)3,5-trans-7-Chloro-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethanol,m.p. 188°-189° C.

Elemental Analysis for C₂₀ H₂₁ Cl₂ NO₃ : Calcd.: C, 60.92; H, 5.37; N,3.55 Found: C, 61.12; H, 5.39; N, 3.72

(2)3,5-trans-7-Chloro-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehyde,an oily compound

¹ H-NMR(CDCl₃) δ: 1.30(3H,d,J=7.0 Hz), 1.56(3H,d,J=6.6 Hz),2.88(1H,ddd,J=17.6,5.4,1.6 Hz), 3.09(1H,ddd,J=17.6,6.6,1.0 Hz),4.37(1H,t,J=6.1 Hz),4.8-5.0(1H,m), 6.02(1H,s), 6.52(1H,d,J=2.4 Hz),7.2-7.8(6H,m)

(3)3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethanol,m.p. 147°-149° C.

Elemental Analysis for C₂₁ H₂₃ Cl₂ NO₃ : Calcd.: C, 61.77; H, 5.68; N,3.43 Found: C, 61.64; H, 5.87; N, 3.54

(4)3,5-trans-7-Chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehyde,an oily compound

¹ H-NMR(CDCl₃) δ: 0.94(3H,d,J=6.8 Hz), 1.03(3H,d,J=6.6 Hz),1.85-2.1(1H,m), 2.90(1H,ddd,J=17.6,5.4,1.4 Hz),3.12(1H,ddd,J=17.6,6.6,1.0 Hz), 3.45(1H,dd,J=13.8,5,6 Hz),4.31(1H,dd,J=13.8,8.2 Hz), 4.4-4.55(1H,m), 6.15(1H,s), 6.54(1H,d,J=2.4Hz), 7.2-7.8(6H,m), 9.84(1H,s)

Reference Example 13,5-trans-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(β-hydroxy)butyric acid ethyl ester ##STR40##

To a solution of diisopropylamine (0.70 ml)in dry tetrahydrofuran (5ml)was added a hexane solution (3.03 ml, 1.64 mol/L)of n-butyllithium attemperatures ranging from -15° C. to -20° C. The mixture was stirred forone hour at the same temperature range. The reaction mixture was cooledto -78° C., to which was added acetic acid ethyl ester (0.49 ml), andthe mixture was stirred for 15 minutes. To the reaction mixture wasadded dropwise for 5 minutes a dry tetrahydrofuran (10 ml) solution of3,5-trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehyde.The mixture was stirred for 30 minutes, to which was added dilutehydrochloric acid (50 ml), followed by extraction with acetic acid ethylester. The organic layer was washed with a saturated aqueous solution ofsodium hydrogencarbonate, which was dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue was purified bymeans of a silica gel column chromatography to afford colorless crystals(1.20 g), m.p. 119°-121° C.

Elemental Analysis for C₂₄ H₂₇ Cl₂ NO₅ : Calcd.: C, 60,01; H, 5.67; N,2.92 Found: C, 60.16; H, 5.78; N, 2.97

Reference Example 23,5-trans-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(β-hydroxy)butyric acid ##STR41##

In substantially the same manner as in Example 15, a non-crystallinesolid was obtained.

¹ H-NMR(CDCl₃) δ: 1.29,1.30(3H,each d,J=7.0 Hz), 1.56,1.57(3H,eachd,J=6.8 Hz), 2.0-2.15(2H,m), 2.45-2.7(2H,m), 4.05-4.2(1H,m),4.2-4.4(1H,m), 4.75-4.95(1H,m), 6.01(1H,s), 6.45-6.55(1H,m),7.2-7.8(6H,m)

Reference Example 3(3RS,5SR,βRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(β-hydroxy)ethanol##STR42##

To a solution of(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid ethyl ester (1.0 g) in ethanol (30 ml) was added sodium borohydride(0.14 g). The mixture was stirred for 4 hours at room temperature. Thereaction mixture was made acid with dilute hydrochloric acid, which wasextracted with acetic acid ethyl ester. The extract solution was washedwith a saturated aqueous solution of sodium hydrogencarbonate, which wasdried over anhydrous magnesium sulfate. The solvent was distilled off,and the residue was purified by means of a silica gel columnchromatography to give colorless crystals (0.62 g), m.p. 229°-230° C.

Elemental Analysis for C₂₀ H₂₁ Cl₂ NO₄ : Calcd.: C, 58.33; H, 5.16; N,3.41 Found: C, 58.49; H, 5.21; N, 3.32

Reference Example 4

Using the compounds obtained in Example 14 and Example 17, bysubstantially the same manner as in Reference Example 3, the compoundsshown in Table 4! were obtained.

                  TABLE 4                                                         ______________________________________                                         ##STR43##                                                                    Compd. No.                                                                            R              Steric Configuration                                   ______________________________________                                        1       (CH.sub.2).sub.2 CH.sub.3                                                                    3RS, 5SR, βRS                                                                       oily                                        .sup.1 HNMR(CDCl.sub.3)δ: 0.97(3H, t, J=7.3Hz), 1.5-1.9(2H, m),         2.0-2.3(3H, m), 2.82(1H, br), 3.4-3.75(3H, m), 3.8-4.05                       (1H, m), 4.18(1H, t, J=6.4Hz), 4.3-4.5(1H, ddd, J=12.6,                       9.8, 6.4Hz), 6.04(1H, s), 6.52(1H, d, J=2.2Hz), 7.2-7.8                       (6H, m)                                                                       2       (CH.sub.2).sub.2 CH.sub.3                                                                    3RS, 5SR, βSR                                                                       oily                                        .sup.1 HNMR(CDCl.sub.3)δ: 0.97(3H, t, J=7.4Hz), 1.5-1.9(2H, s),         2.0-2.3(3H, m), 3.4-3.8(3H, m), 3.9-4.05(1H, m), 4.20                         (1H, t, J=5.7Hz), 4.3-4.5(1H, ddd, J=12.6, 9.8, 6.4Hz),                       6.03(1H, s), 6.53(1H, d, J=2.2Hz), 7.2-7.8(6H, m)                             3       CH.sub.2 CH(CH.sub.2).sub.2                                                                  3RS, 5SR, βRS                                                                       oily                                        .sup.1 HNMR(CDCl.sub.3)δ: 0.93(3H, d, J=6.6Hz), 1.03(3H, d, J=          6.6Hz), 1.8-2.15(3H, m), 3.35-3.75(3H, m), 3.85-4.05                          (1H, m), 4.19(1H, t, J=6.4Hz), 4.33(1H, dd, J=13.6,                           8.4Hz), 6.14(1H, s), 6.52(1H, d, J=2.2Hz), 7.2-7.8(6H, m)                     ______________________________________                                    

Reference Example 53,5-trans-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(γ-hydroxy)butanol ##STR44##

By subjecting the compound obtained in Reference Example 1 tosubstantially the same procedure as in Reference Example 3, anon-crystalline solid compound was obtained.

¹ H-NMR(CDCl₃) δ: 1.30(3H,d,J=7.0 Hz), 1.56(3H,d,J=6.6 Hz),1.6-1.9(2H,m), 2.0-2.2(2H,m), 3.8-3.95(2H,m), 4.0-4.2(2H,m),4.75-4.95(1H,m), 6.02(1H,s), 6.5-6.6(1H,m), 7.2-7.8(6H,m)

Example 18 N-(3RS,5SR,αSR)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolyl!aminoaceticacid ethyl ester ##STR45##

In N-dimethylformamide (10 ml) were dissolved(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolicacid (0.3 g) obtained in Example 1 and glycine ethyl ester hydrochloride(0.12 g). To the solution were added diethyl cyanophosphonate (0.15 g)and triethylamine (0.24 ml) under ice-cooling. The mixture was stirredfor 30 minutes at room temperature, which was subjected to extraction bythe addition of water (100 ml) and ethyl acetate (100 ml). The ethylacetate layer was washed with 1N hydrochloric acid and an aqueoussolution of sodium hydrogencarbonate, which was then dried overanhydrous magnesium sulfate, followed by distilling off the solventunder reduced pressure. The residue was purified by means of a silicagel column chromatography (hexane:ethyl acetate=1:1) to afford N-(3RS.5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolyl)aminoaceticacid ethyl ester (0.30 g) as prisms, m.p. 157°-159° C.

Elemental Analysis for C₂₄ H₂₆ Cl₂ N₂ O₆ : Calcd.: C, 56,59; H, 5.14; N,5.50 Found: C, 56.60; H, 5.21; N, 5.52

Example 19 N-(3RS,5SR,αSR)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolyl!aminoaceticacid ##STR46##

In ethanol (10 ml) was dissolved N-(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolyl!aminoaceticacid ethyl ester (0.2 g). To the solution was added 1N sodium hydroxideaqueous solution (2 ml), which was stirred for 15 minutes. To themixture was added 1N hydrochloric acid (100 ml) to make the solutionacid, followed by extraction with ethyl acetate (100 ml). The ethylacetate layer was washed with water, then dried over anhydrous magnesiumsulfate, followed by distilling off the solvent under reduced pressureto afford N-(3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolyl!aminoaceticacid (0.18 g) as crystals, m.p. 142°-145° C.

Elemental Analysis for C₂₂ H₂₂ Cl₂ N₂ O₆.1/4H₂ O: Calcd.: C, 54.39; H,4.66; N, 5.77 Found: C, 54.29; H, 4.61; N, 5.77

Example 20 N-(E)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-acetyl!aminoaceticacid ethyl ester ##STR47##

To a solution of(E)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-acetyl!aminoaceticacid (0.3 g) and glycine ethyl ester hydrochloride (0.124 g) indimethylformamide (10 ml) were added diethyl cyanophosphonate (0.152 g)and triethylamine (0.25 ml). The mixture was stirred for 30 minutes atroom temperature. To the reaction mixture was addled acetic acid ethylester, which was washed with dilute hydrochloric acid and a saturatedaqueous solution of sodium hydrogencarbonate, then the solvent wasdistilled off. The residue was purified by means of a silica gel columnchromatography to yield colorless crystals (0.35 g), m.p. 207°-208° C.

Elemental Analysis for C₂₄ H₂₄ Cl₂ N₂ O₅ : Calcd.: C, 58.67; H, 4.92; N,5.70 Found: C, 58.62; H, 4.97; N, 5.68

Example 21

N-(E)-7-Chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-Δ(3,α)-acetyl)aminoaceticacid ##STR48##

To a solution of the compound (0.25 g) obtained in Example 20 in ethanol(20 ml) was added a 1N aqueous solution of sodium hydroxide (4 ml). Themixture was stirred for 30 minutes at room temperature. The reactionmixture was made acid with dilute hydrochloric acid, which was extractedwith acetic acid ethyl ester. The extract was washed with water anddried over anhydrous magnesium sulfate. The solvent was distilled off,and the residue was recrystallized from hexane to give colorlesscrystals (0.21 g), m.p. 217°-221° C. (decomp.)

Elemental Analysis for C₂₂ H₂₀ Cl₂ N₂ O₅.0.5H₂ O: Calcd.: 55.94; H,4.48; N, 5.93 Found: 56.17; H, 4.60; N, 6.05

Example 22

Starting from the compound obtained in Example 13, the compounds shownin Table 5! were obtained by substantially the same procedures as inExample 25 and Example 26.

                                      TABLE 5                                     __________________________________________________________________________     ##STR49##                                                                    Compd.         m.p. Molecular                                                                              Elemental Analysis (Found)                       No. R.sub.1 R.sub.2                                                                          (°C.)                                                                       Formuula C   H   N                                        __________________________________________________________________________    1   (CH.sub.2).sub.2 CH.sub.3                                                             C.sub.2 H.sub.5                                                                  203-205                                                                            C.sub.24 H.sub.24 Cl.sub.2 N.sub.2 O.sub.5                                             58.67                                                                             4.98                                                                              5.70                                                                  (58.48                                                                            5.08                                                                              5.64)                                    2   (CH.sub.2).sub.2 CH.sub.3                                                             H  210-213                                                                            C.sub.22 H.sub.20 Cl.sub.2 N.sub.2 O.sub.5                                             57.03                                                                             4.35                                                                              6.05                                                    (decomp.)     (56.95                                                                            4.41                                                                              6.23)                                    3   CH.sub.2 CH(CH.sub.3).sub.2                                                           C.sub.2 H.sub.5                                                                  182-185                                                                            C.sub.25 H.sub.26 Cl.sub.2 N.sub.2 O.sub.5                                             59.41                                                                             5.19                                                                              5.54                                                                  (58.90                                                                            5.17                                                                              5.56)                                    4   CH.sub.2 CH(CH.sub.3).sub.2                                                           H  219-221                                                                            C.sub.23 H.sub.22 Cl.sub.2 N.sub.2 O.sub.5                                             57.87                                                                             4.65                                                                              5.87                                                    (decomp.)     (57.57                                                                            4.73                                                                              5.95)                                    __________________________________________________________________________

Assay Method of Squalene Synthetase Inhibitory Activity

The squalene synthetase inhibitory activity was assayed as follows withthe enzyme solutions described in the subsequent Experimental Examples 1and 2.

More specifically, an enzyme solution (protein content 0.8 ug) preparedin Experimental Example 1 or 2 was added to a solution (total volume 50μl)) containing 5 μM 1-³ H! farnesyl pyrophosphate (specific activity 25μCi/mole), 1 mM NADPH, 5 mM MgCl₂, 6 mM glutathione, a 100 mM buffersolution of potassium phosphate (pH 7.4) and a test drug (used as anaqueous solution or a DMSO solution), then the reaction was allowed toproceed at 37° C. for 45 minutes. To the reaction mixture was added 150μl of a mixture of chloroform and methanol (1:2) to suspend thereaction, followed by adding 50 μl of chloroform and 50 μl of a 3Naqueous solution of sodium hydroxide. 50 μl of the chloroform layer(lower layer) containing the reaction mixture having squalene as theprincipal component and 3 ml of toluene-based liquid scintillator weremixed, and its radioactivity was determined by means of a liquidscintillation counter.

The squalene synthetase inhibitory activity was expressed in terms ofthe concentration inhibiting by 50% the radioactivity taken into thechloroform layer (IC₅₀, molar concentration (M)).

Experimental Example 1

Preparation of rat-derived enzyme

An SD male rat (6 week old) was killed by bleeding, and its liver wasexcised. About 10 g of the liver was washed with a saline solutioncooled with ice, which was then homogenized in 15 ml of an ice-cooledbuffer solution 100 mM potassium phosphate (pH 7.4), 15 mM nicotinamide,2 mM MgCl₂ !, followed by centrifugation for 20 minutes (4° C.) with10000×g. The supernatant layer was separated and subjected to furthercentrifugation for 90 minutes (4° C.) at 105000×g. The sediment was thensuspended in an ice-cooled 100 mM phosphate buffer solution (pH 7.4),which was again subjected to centrifugation for 90 minutes (4° C.) at105000×g. The sediment thus obtained (microsome fraction) was suspendedin an ice-cooled 100 mM potassium phosphate buffer (pH 7.4) (about 40mg/ml protein concentration, determined with BCA protein assay kit ofPias Co., Ltd.). This suspension was used as the enzyme solution.

Experimental Example 2

Preparation of human-derived enzyme

Human hepatic carcinoma cells HepG2 (about 1×10⁹ cells) obtained byincubation in a Dulbecco-modified Eagle's medium (37° C. in the presenceof 5% CO₂) were suspended in 10 ml of an ice-cooled buffer solution 100mM potassium phosphate buffer (pH 7.4), 30 mM nicotinamide and 2.5 mMMgCl₂ !. The cells were crushed by means of ultrasonication (for 30seconds, twice). From the sonicate thus obtained, the microsome fractionwas obtained by the same procedure as in Experiment Example 1, which wassuspended in an ice-cooled 100 mM potassium phosphate buffer (pH 7.4)(about 4 mg/ml protein concentration). This suspension was used as theenzyme solution. The results are shown in Table 6!.

                  TABLE 6                                                         ______________________________________                                        Compd.  Rat-derived enzyme                                                                         Human-derived enzyme                                     No.     (10.sup.-7 M)                                                                              (10.sup.-7 M)                                            ______________________________________                                        Example                                                                       12      3.1                                                                   13-4    0.76                                                                  13-8    3.6                                                                   15      2.4                                                                   16      2.8                                                                   17-5    5.3                                                                   17-6    6.0                                                                   17-7    2.3                                                                   17-8    3.3                                                                   21      1.9                                                                   22-2    1.3                                                                   22-4    0.98         0.47                                                     R. Ex.                                                                        3       9.9                                                                   4-1     9.7                                                                   4-2     8.8                                                                   ______________________________________                                    

Formulation Examples

A squalene synthetase inhibiting agents containing, as its effectivecomponent, a condensed 7-membered compound represented by the formula(I) of this invention or a salt thereof, in the case where it is used asa therapeutic agent of hypercholesteremia, can be formulated inaccordance with, for example, the following prescriptions.

    ______________________________________                                        1. Capsules                                                                   ______________________________________                                        (1) Compound obtained in Example 13-4                                                                   10 mg                                               (2) Lactose               90 mg                                               (3) Microcrystalline cellulose                                                (4) Magnesium stearate    70 mg                                               One capsule               180 mg                                              ______________________________________                                    

(1), (2) and (3) and one half of (4) were blended and the mixture wasgranulated, to which was added the balance of (4). The mixture wasfilled in a gelatin capsule.

    ______________________________________                                        2. Tablets                                                                    ______________________________________                                        (1) Compound obtained in Example 13-4                                                                   10 mg                                               (2) Lactose               35 mg                                               (3) Corn starch           150 mg                                              (4) Microcrystalline cellulose                                                                          30 mg                                               (5) Magnesium stearate    5 mg                                                One tablet                230 mg                                              ______________________________________                                    

(1), (2) and (3) and two thirds of (4) and one half of (5) were blendedand the mixture was granulated, to which were added the balance of (4)and (5). The mixture was subjected to compression-molding to providetablets.

    ______________________________________                                        3. Injections                                                                 ______________________________________                                        (1) Sodium salt of the compound                                                                        10 mg                                                obtained in Example 13-4                                                      (2) Inositol             100 mg                                               (3) Benzyl alcohol       20 mg                                                One ampoule              130 mg                                               ______________________________________                                    

(1), (2) and (3) were dissolved in distilled water for injection to makethe whole volume 2 ml, which was put in an ampoule, and the ampoule wassealed. All the processes were conducted under sterilized conditions.

    ______________________________________                                        4. Capsules                                                                   ______________________________________                                        (1) Compound obtained in Example 22-4                                                                   10 mg                                               (2) Lactose               90 mg                                               (3) Microcrystalline cellulose                                                                          70 mg                                               (4) Magnesium stearate    10 mg                                               One capsule               180 mg                                              ______________________________________                                    

(1), (2) and (3) and one half of (4) were blended and the mixture wasgranulated, to which was added the balance of (4). The mixture wasfilled in a gelatin capsule.

    ______________________________________                                        5. Tablets                                                                    ______________________________________                                        (1) Compound obtained in Example 22-4                                                                   10 mg                                               (2) Lactose               35 mg                                               (3) Corn starch           150 mg                                              (4) Microcrystalline cellulose                                                                          30 mg                                               (5) Magnesium stearate    5 mg                                                One tablet                230 mg                                              ______________________________________                                    

(1), (2) and (3) and two thirds of (4) and one half of (5) were blendedand the mixture was granulated, to which were added the balance of (4)and (5). The mixture was subjected to compression-molding to providetablets.

    ______________________________________                                        6. Injections                                                                 ______________________________________                                        (1) Sodium salt of the compound                                                                        10 mg                                                obtained in Example 22-4                                                      (2) Inositol             100 mg                                               (3) Benzyl alcohol       20 mg                                                One ampoule              130 mg                                               ______________________________________                                    

(1), (2) and (3) were dissolved in distilled water for injection to makethe whole volume 2 ml, which was put in an ampoule, and the ampoule wassealed. All the processes were conducted under sterilized conditions.

What is claimed is:
 1. A compound represented by the formula (I) ##STR50## wherein R₁ stands for H or a hydrocarbon group which may be substituted by one to five substituents selected from the group consisting of(1) phenyl, naphthyl, anthryl, phenanthryl, or acenaphthylenyl which may be substituted by one or two substituents selected from the group consisting of (i) C₁₋₃ alkoxy groups, (ii) halogen atoms and, (iii) C₁₋₃ alkyl groups, (2) C₃₋₇ cycloalkyl groups which may be substituted by one or two substituents selected from the group consisting of (i) C₁₋₃ alkoxy groups, (ii) halogen atoms, and (iii) C₁₋₃ alkyl groups, (3) C₃₋₆ cycloalkenyl groups which may be substituted by one or two substituents selected from the group consisting of (i) C₃₋₆ alkoxy groups, (ii) halogen atoms, and (iii) C₁₋₃ alkyl groups, (4) furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo b!thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo 1,2-b!pyridazinyl, pyrazolo 1,5-a!pyridyl, imidazo 1,2-a!pyridyl, imidazo 1,5-a!pyridyl, imidazo 1,2-b!pyridazinyl, imidazo 1,2-a!pyrimidinyl, 1,2,4-triazolo 4,3-a!pyridyl, 1,2,4-triazolo 4,3-b!pyridazinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, or piperazinyl which may be substituted by C₁₋₃ alkyl groups, (5) amino groups which may be substituted by C₁₋₃ alkyl group(s), (6) hydroxy groups which may be substituted by a C₁₋₃ alkyl group, (7) thiol groups which may be substituted by a C₁₋₃ alkyl group, and (8) halogens; R₂ and R₃ independently stand for H, an alkyl group which may be substituted by substituents selected from the group consisting of (1) halogen atoms and (2) C₁₋₄ lower alkoxy groups, a phenyl group which may be substituted by 1 to 3 substituents selected from the group consisting of(1) halogen atoms, (2) C₁₋₄ alkyl groups which may be substituted by 1 to 5 halogen atoms, (3) C₁₋₄ alkoxy groups which may be substituted by 1 to 5 halogen atoms, (4) hydroxyl groups which may be substituted by a substituent selected from the group consisting of (i) C₁₋₄ alkyl groups, (ii) C₃₋₆ cycloalkyl groups, (iii) phenyl, 1-naphthyl or 2-naphthyl, and (iv) benzyl or phenethyl, (5) nitro group and (6) cyano group; or furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo b!thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo 1,2-b!pyridazinyl, pyrazolo 1,5-a!pyridyl, imidazo 1,2-a!pyridyl, imidazo 1,5-a!pyridyl, imidazo 1,2-b!pyridazinyl, imidazo 1,2-a!pyrimidinyl, 1,2,4-triazolo 4,3-a!pyridyl, or 1,2,4-triazolo 4,3-b!pyridazinyl, which may be substituted by C₁₋₃ alkyl groups; Z stands for methine, vinylene, propenylene, butenylene, butadienylene, methylpropenylene, ethylbutenylene, propylbutenylene, methylbutadienylene, ethylbutadienylene, propylbutadienylene, pentenylene, hexenylene, heptenylene, pentadienylene, hexadienylene, heptadienylene, or --Z'--CH(OH)--(Z' stands for a bond or a straight-chain or branched C₁₋₆ alkylene group); the symbol ..... stands for a double bond or a single bond; Y stands for an optionally esterified carboxyl group, a carbamoyl group which may be substituted by one or two of substituents selected from the group consisting of(1) lower (C₁₋₆) alkyl groups which may be substituted by 1to 3 substituents selected from the group consisting of (i) carboxyl group which may be esterified by a lower (C₁₋₅) alkyl group, (ii) furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl or imidazolyl, (iii) amino group, (iv) hydroxyl group and (v) phenyl group, (2) C₃₋₆ cycloalkyl groups which may be substituted by 1 to 3 substituents selected from the group consisting of (i) carboxyl groups which may be esterified by a lower (C₁₋₅) alkyl group, (ii) furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl or imidazolyl, (iii) amino group, (iv) hydroxyl group and (v) phenyl group, (3) phenyl, 1-naphthyl, or 2-naphthyl which may be substituted by substituents selected from the group consisting of (i) halogen atoms and (ii) carboxyl groups which may be esterified by a lower (C₁₋₄) alkyl group, (4) benzyl or phenethyl which may be substituted by the substituents selected from the group consisting of (i) halogen atoms and (ii) carboxyl groups which may be esterified by a C₁₋₄ alkyl group, or two substituents on the nitrogen atom of the carbamoyl group may form, together with the nitrogen atom, a cyclic amino group selected from the group consisting of (1) 1-azetidinyl, (2) 1-pyrrolidinyl, (3) piperidino, (4) morpholino and (5) 1-piperazinyl; a hydroxyl group which may be substituted by a substituent selected from the group consisting of(1) C₁₋₄ alkyl groups, (2) C₃₋₆ cycloalkyl groups or (3) phenyl, 1-naphthyl or 2-naphthyl which may be substituted by substituents selected from the group consisting of (i) halogen atoms and (ii) carboxyl groups which may be esterified by a C₁₋₄ alkyl group, or (4) benzyl or phenethyl which may be substituted by substituents selected from the group consisting of (i) halogen atoms and (ii) carboxyl groups which may be esterified by a C₁₋₄ alkyl group, an amino group which may be substituted by substituents selected from the group consisting of(1) C₁₋₄ alkyl groups, (2) C₃₋₆ cycloalkyl groups, (3) phenyl, 1-naphthyl or 2-naphthyl which may be substituted by substituents selected from the group consisting of (i) halogen atoms and (ii) carboxyl group which may be esterified by C₁₋₄ alkyl group, (4) benzyl or phenethyl which may be substituted by the substituents selected from the group consisting of (i) halogen atoms and (ii) carboxyl group which may be esterified by C₁₋₄ alkyl group, or two substituents on the nitrogen atom of the amino group may form, together with the nitrogen atom, a cyclic amino group selected from the groups consisting of (1) 1-azetidinyl, (2) 1-pyrrolidinyl, (3) piperidino, (4) morpholino and (5) 1-piperazinyl; and wherein the ring A may be substituted by one or two substituents selected from the group consisting of(1) hydroxyl group, (2) halogens, (3) nitro group, (4) cyano group, (5) C₁₋₄ alkyl groups, and (6) C₁₋₄ alkoxy groups, or a pharmaceuticallyacceptable salt thereof.
 2. The compound or the salt thereof as claimed in claim 1, wherein R₁ is an aliphatic chain hydrocarbon group.
 3. The compound or the salt thereof as claimed in claim 2, wherein R₁ is an alkyl group.
 4. The compound or the salt thereof as claimed in claim 3, wherein R₁ is a lower alkyl group.
 5. The compound or the salt thereof as claimed in claim 1, wherein R₂ or R₃ is a phenyl group, which may be substituted by 1 to 3 substituents selected from the group consisting of (1) halogen atoms,(2) C₁₋₄ alkyl groups which may be substituted by one to five halogen atoms, (3) C₁₋₄ alkoxy groups which may be substituted by one to five halogen atoms, (4) hydroxyl groups which may be substituted by a substituent selected from the group consisting of (i) C₁₋₄ alkyl groups, (ii) C₃₋₆ cycloalkyl groups, (iii) phenyl, 1-naphthyl or 2-naphthyl and (iv) benzyl or phenethyl, (5) nitro groups and (6) cyano groups.
 6. The compound or the salt thereof as claimed in claim 1, wherein Z is a C₁₋₄ alkenyl group.
 7. The compound or the salt thereof as claimed in claim 1, in which Y is an optionally esterified carboxyl group or a carbamoyl group which may be substituted by one or two of substituents selected from the group consisting of(1) lower (C₁₋₆) alkyl groups which may be substituted by 1 to 3 substituents selected from the group consisting of (i) carboxyl groups which may be esterified by a lower (C₁₋₅) alkyl group, (ii) furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl or imidazolyl, (iii) amino group, (iv) hydroxyl group and (v) phenyl group, (2) C₃₋₆ cycloalkyl groups which may be substituted by 1 to 3 substituents selected from the group consisting of (i) carboxyl groups which may be esterified by a lower (C₁₋₅) alkyl group, (ii) furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl or imidazolyl, (iii) amino group, (iv) hydroxyl group and (v) phenyl group, (3) phenyl, 1-naphthyl, or 2-naphthyl which may be substituted by substituents selected from the group consisting of (i) halogen atoms and (ii) carboxyl groups which may be esterified by a lower (C₁₋₄) alkyl group, and (4) benzyl or phenethyl which may be substituted by substituents selected from the group consisting of (i) halogen atoms and (ii) carboxyl groups which may be esterified by a lower (C₁₋₄) alkyl group, or two substituents on a nitrogen atom may form a cyclic amino group selected from a the group consisting of (1) 1-azetidinyl, (2) 1-pyrrolidinyl, (3) piperidino, (4) morpholino and (5) 1-piperazinyl.
 8. The compound or the salt thereof as claimed in claim 1, in which the symbol ......... is a double bond.
 9. A squalene synthetase inhibitor which comprises the compound or a salt thereof as claimed in claim 1 and a pharmaceutically acceptable carrier.
 10. A compound as claimed in claim 1 which is (3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionic acid or a pharmaceutically acceptable salt thereof.
 11. A compound as claimed in claim 1 which is (3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionic acid or a pharmaceutically acceptable salt thereof.
 12. A compound as claimed in claim 1, which is (3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid or a pharmaceutically acceptable salt thereof.
 13. A compound as claimed in claim 1, which is (3RS,5RS,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid or a pharmaceutically acceptable salt thereof.
 14. A compound as claimed in claim 1, which is (3RS,5RS,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid or a pharmaceutically acceptable salt thereof.
 15. A compound as claimed in claim 1, which is (3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid or a pharmaceutically acceptable salt thereof.
 16. A compound as claimed in claim 1, which is (Z)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-acetic acid or a pharmaceutically acceptable salt thereof.
 17. A compound as claimed in claim 1, which is (E)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-acetic acid or a pharmaceutically acceptable salt thereof.
 18. A compound as claimed in claim 1, which is (Z)-7-chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-acetic acid or a pharmaceutically acceptable salt thereof.
 19. A compound as claimed in claim 1, which is (E)-7-chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-acetic acid or a pharmaceutically acceptable salt thereof.
 20. A compound as claimed in claim 1, which is (Z)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-Δ(3,α)-acetic acid or a pharmaceutically acceptable salt thereof.
 21. A compound as claimed in claim 1, which is (E)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-α(3,α)-acetic acid or a pharmaceutically acceptable salt thereof.
 22. A compound as claimed in claim 1, which is (3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionic acid or a pharmaceutically acceptable salt thereof.
 23. A compound as claimed an claim 1, which is (3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-2-oxo-1-propyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionic acid or a pharmaceutically acceptable salt thereof.
 24. A compound as claimed in claim 1, which is (3RS,5SR,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionic acid or a pharmaceutically acceptable salt thereof.
 25. A compound as claimed an claim 1, which is (3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-(α-hydroxy)propionic acid or a pharmaceutically acceptable salt thereof. 